Mitotic kinesin inhibitors

ABSTRACT

The present invention relates to bicyclic tetrahydropyridine compounds that are useful for treating cellular proliferative diseases, for treating disorders associated with KSP kinesin activity, and for inhibiting KSP kinesin. The invention also related to compositions which comprise these compounds, and methods of using them to treat cancer in mammals.

BACKGROUND OF THE INVENTION

This invention relates to bicyclic dihydropyrrole derivatives that areinhibitors of mitotic kinesins, in particular the mitotic kinesin KSP,and are useful in the treatment of cellular proliferative diseases, forexample cancer, hyperplasias, restenosis, cardiac hypertrophy, immunedisorders and inflammation.

Among the therapeutic agents used to treat cancer are the taxanes andvinca alkaloids. Taxanes and vinca alkaloids act on microtubules, whichare present in a variety of cellular structures. Microtubules are theprimary structural element of the mitotic spindle. The mitotic spindleis responsible for distribution of replicate copies of the genome toeach of the two daughter cells that result from cell division. It ispresumed that disruption of the mitotic spindle by these drugs resultsin inhi bition of cancer cell division, and induction of cancer celldeath. However, microtubules form other types of cellular structures,including tracks for intracellular transport in nerve processes. Becausethese agents do not specifically target mitotic spindles, they have sideeffects that limit their usefulness.

Improvements in the specificity of agents used to treat cancer is ofconsiderable interest because of the therapeutic benefits which would berealized if the side effects associated with the administration of theseagents could be reduced. Traditionally, dramatic improvements in thetreatment of cancer are associated with identification of therapeuticagents acting through novel mechanisms. Examples of this include notonly the taxanes, but also the camptothecin class of topoisomerase Iinhibitors. From both of these perspectives, mitotic kinesins areattractive targets for new anti-cancer agents.

Mitotic kinesins are enzymes essential for assembly and function of themitotic spindle, but are not generally part of other microtubulestructures, such as in nerve processes. Mitotic kinesins play essentialroles during all phases of mitosis. These enzymes are “molecular motors”that transform energy released by hydrolysis of ATP into mechanicalforce which drives the directional movement of cellular cargoes alongmicrotubules. The catalytic domain sufficient for this task is a compactstructure of approximately 340 amino acids. During mitosis, kinesinsorganize microtubules into the bipolar structure that is the mitoticspindle. Kinesins mediate movement of chromosomes along spindlemicrotubules, as well as structural changes in the mitotic spindleassociated with specific phases of mitosis. Experimental perturbation ofmitotic kinesin function causes malformation or dysfunction of themitotic spindle, frequently resulting in cell cycle arrest and celldeath.

Among the mitotic kinesins which have been identified is KSP. KSPbelongs to an evolutionarily conserved kinesin subfamily of plusend-directed microtubule motors that assemble into bipolar homotetramersconsisting of antiparallel homodimers. During mitosis KSP associateswith microtubules of the mitotic spindle. Microinjection of antibodiesdirected against KSP into human cells prevents spindle pole separationduring prometaphase, giving rise to monopolar spindles and causingmitotic arrest and induction of programmed cell death. KSP and relatedkinesins in other, non-human, organisms, bundle antiparallelmicrotubules and slide them relative to one another, thus forcing thetwo spindle poles apart. KSP may also mediate in anaphase B spindleelongation and focussing of microtubules at the spindle pole.

Human KSP (also termed HsEg5) has been described [Blangy, et al., Cell,83:1159-69 (1995); Whitehead, et al., Arthritis Rheum., 39:1635-42(1996); Galgio et al., J. Cell Biol., 135:339-414 (1996); Blangy, etal., J Biol. Chem., 272:19418-24 (1997); Blangy, et al., Cell MotilCytoskeleton, 40:174-82 (1998); Whitehead and Rattner, J. Cell Sci.,111:2551-61 (1998); Kaiser, et al., JBC 274:18925-31 (1999); GenBankaccession numbers: X85137, NM004523 and U37426], and a fragment of theKSP gene (TIRIP5) has been described [Lee, et al., Mol Endocrinol.,9:243-54 (1995); GenBank accession number LA0372]. Xenopus KSP homologs(Eg5), as well as Drosophila K-LP61 F/KRP 130 have been reported.

Certain quinazolinones have recently been described as being inhibitorsof KSP (PCT Publ. WO 01/30768, May 3, 2001).

Mitotic kinesins are attractive targets for the discovery anddevelopment of novel mitotic chemotherapeutics. Accordingly, it is anobject of the present invention to provide compounds, methods andcompositions useful in the inhibition of KSP, a mitotic kinesin.

SUMMARY OF THE INVENTION

The present invention relates to bicyclic tetrahydropyridinederivatives, that are useful for treating cellular proliferativediseases, for treating disorders associated with KSP kinesin activity,and for inhibiting KSP kinesin. The compounds of the invention may beillustrated by the Formula I:

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention are useful in the inhibition of mitotickinesins and are illustrated by a compound of Formula I:

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

-   a is 0 or 1;-   b is 0 or 1;-   m is 0, 1, or 2;-   n is 0 or 1;-   r is 0 or 1;-   s is 0 or 1;-   u is 2, 3, 4or 5;-   v is 1, 2or 3;-   a dashed line represents an optional double bond, provided that one    and only one double bond is present in the ring;-   X is selected from: —(CR⁸R⁸)_(v)—, —SO₂—, —SO— and —C(═O)—;-   Y is selected from: O, N(R^(c)), S, —C(═O)—, —CR⁸R⁸—,    —N(R^(c))C(═O)— and —N(R^(c))CR⁸R⁸—; or-   X and Y are combined to form —C(R⁸)═C(R⁸)—;-   Z is selected from: —C(═O)—, —C(═S)—, —SO₂—, —SO— and —C(R⁸)(R⁹)—;    or-   Y and Z are combined to form —N═C(R⁸)—;-   R¹ and R⁴ are independently selected from:

1) aryl,

2) C₁-C₆ aralkyl,

3) C₃-C₈ cycloalkyl, and

4) heterocyclyl,

-   said aryl, cycloalkyl, aralkyl and heterocyclyl is optionally    substituted with one or more substituents selected from R¹⁰;-   R², R^(3a), R^(3b), R⁵, R⁶ and R⁷ are independently selected from:

1) H,

2) C₁-C₁₀ alkyl,

3) aryl,

4) C₂-C₁₀ alkenyl,

5) C₂-C₁₀ alkynyl,

6) C₁-C₆ perfluoroalkyl,

7) C₁-C₆ aralkyl,

8) C₃-C₈ cycloalkyl, and

9) heterocyclyl,

-   said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, aralkyl and    heterocyclyl is optionally substituted with one or more substituents    selected from R¹⁰; or-   R^(3a) and R^(3b) or R⁵ and R⁶ attached to the same carbon atom are    combined to form —(CH₂)_(u)— wherein one of the carbon atoms is    optionally replaced by a moiety selected from O, S(O)_(m),    —N(R^(a))C(O)—, —N(R^(b))— and —N(COR^(a))—;-   R⁸ and R⁹ is independently selected from:

1) H,

2) (C═O)_(a)O_(b)C₁-C₁₀ alkyl,

3) (C═O)_(a)O_(b)aryl,

4) C₂-C₁₀ alkenyl,

5) C₂-C₁₀ alkynyl,

6) (C═O)_(a)O_(b) heterocyclyl,

7) CO₂H,

8) halo,

9) CN,

10) OH,

11) O_(b)C₁-C₆ perfluoroalkyl,

12) O_(a)(C═O)_(b)NR¹²R¹³,

13) S(O)_(m)R^(a),

14) S(O)₂NR¹²R¹³,

15) CHO,

16) (N═O)R¹²R¹³, and

17) (C═O)_(a)O_(b)C₃-C₈ cycloalkyl,

-   said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl    optionally substituted with one or more substituents selected from    R¹¹;-   R¹⁰ is independently selected from:

1) (C═O)_(a)O_(b)C₁-C₁₀ alkyl,

2) (C═O)_(a)O_(b)aryl,

3) C₂-C₁₀ alkenyl,

4) C₂-C₁₀ alkynyl,

5) (C═O)_(a)O_(b) heterocyclyl,

6) CO₂H,

7) halo,

8) CN,

9) OH,

10) O_(b)C₁-C₆ perfluoroalkyl,

11) O_(a)(C═O)_(b)NR¹²R¹³,

12) S(O)_(m)R^(a),

13) S(O)₂NR¹²R¹³,

14) oxo,

15) CHO,

16) (N═O)R¹²R¹³,

17) (C═O)_(a)O_(b)C₃-C₈ cycloalkyl, and

18) —OPO(OH)₂;

-   said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl    optionally substituted with one or more substituents selected from    R¹¹;-   R¹¹ is selected from:

1) (C═O)_(r)O_(s)(C₁-C₁₀)alkyl,

2) O_(r)(C₁-C₃)perfluoroalkyl,

3) (C₀-C₆)alkylene-S(O)_(m)R^(a),

4) oxo,

5) OH,

6) halo,

7) CN,

8) (C═O)_(r)O_(s)(C₂-C₁₀)alkenyl,

9) (C═O)_(r)O_(s)(C₂-C₁₀)alkynyl,

10) (C═O)_(r)O_(s)(C₃-C₆)cycloalkyl,

11) (C═O)_(r)O_(s)(C₀-C₆)alkylene-aryl,

12) (C═O)_(r)O_(s)(C₀-C₆)alkylene-heterocyclyl,

13) (C═O)_(r)O_(s)(C₀-C₆)alkylene-N(R^(b))₂,

14) C(O)R^(a),

15) (C₀-C₆)alkylene-CO₂R^(a),

16) C(O)H,

17) (C₀-C₆)alkylene-CO₂H,

18) C(O)N(R^(b))₂,

19) S(O)_(m)R^(a),

20) S(O)₂N(R^(b))₂ and

21) —OPO(OH)₂;

-   said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylene and    heterocyclyl is optionally substituted with up to three substituents    selected from R^(b), OH, (C₁-C₆)alkoxy, halogen, CO₂H, CN,    O(C═O)C₁-C₆ alkyl, oxo, and N(R^(b))₂;-   R¹² and R¹³ are independently selected from:

1) H,

2) (C═O)O_(b)C₁-C₁₀ alkyl,

3) (C═O)O_(b)C₃-C₈ cycloalkyl,

4) (C+O)O_(b)aryl,

5) (C═O)O_(b)heterocyclyl,

6) C₁-C₁₀ alkyl,

7) aryl,

8) C₂-C₁₀ alkenyl,

9) C₂-C₁₀ alkynyl,

10) heterocyclyl,

11) C₃-C₈ cycloalkyl,

12) SO₂R^(a), and

13) (C═O)NR^(b) ₂,

-   said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl is    optionally substituted with one or more substituents selected from    R¹¹, or-   R¹² and R¹³ can be taken together with the nitrogen to which they    are attached to form a monocyclic or bicyclic heterocycle with 3-7    members in each ring and optionally containing, in addition to the    nitrogen, one or two additional heteroatoms selected from N, O and    S, said monocyclic or bicyclic heterocycle optionally substituted    with one or more substituents selected from R¹¹;-   R¹⁴ is independently selected from:

1) (C═O)_(a)O_(b)C₁-C₁₀ alkyl,

2) (C═O)_(a)O_(b)aryl,

3) C₂-C₁₀ alkenyl,

4) C₂-C₁₀ alkynyl,

5) (C═O)_(a)O_(b) heterocyclyl,

6) CO₂H,

7) halo,

8) CN,

9) OH,

10) O_(b)C₁-C₆ perfluoroalkyl,

11) O_(a)(C═O)_(b)NR¹²R¹³,

12) S(O)_(m)R^(a),

13) S(O)₂NR¹²R¹³,

14) oxo,

15) CHO,

16) (N═O)R¹²R¹³,

17) (C═O)_(a)O_(b)C₃-C₈ cycloalkyl, and

18) —OPO(OH)₂;

-   said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl    optionally substituted with one or more substituents selected from    R¹¹;-   R^(a) is (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, aryl, or heterocyclyl,    optionally substituted with one to three substituents selected from    R¹⁴;-   R^(b) is H, (C₁-C₆)alkyl, aryl, heterocyclyl, (C₃-C₆)cycloalkyl,    (C═O)OC₁-C₆ alkyl, (C═O)C₁-C₆ alkyl or S(O)₂R^(a), optionally    substituted with one to three substituents selected from R¹⁴;-   R^(c) and R^(c′) are independently selected from: H, (C₁-C₆)alkyl,    aryl, heterocyclyl and (C₃-C₆)cycloalkyl, optionally substituted    with one, two or three substituents selected from R¹⁰, or-   R^(c) and R^(c′) can be taken together with the nitrogen to which    they are attached to form a monocyclic or bicyclic heterocycle with    3-7 members in each ring and optionally containing, in addition to    the nitrogen, one or two additional heteroatoms selected from N, O    and S, said monocyclic or bicyclic heterocycle optionally    substituted with one, two or three substituents selected from R¹¹;-   R^(d) and R^(d′) are independently selected from: (C₁-C₆)alkyl,    (C₁-C₆)alkoxy and NR^(b) ₂, or-   R^(d) and R^(d′) can be taken together with the phosphorous to which    they are attached to form a monocyclic heterocycle with 5-7 members    the ring and optionally containing, in addition to the phosphorous,    one or two additional heteroatoms selected from NR^(e), O and S,    said monocyclic heterocycle optionally substituted with one, two or    three substituents selected from R¹¹; and-   R^(e) is selected from: H and (C₁-C₆)alkyl.

Another embodiment of the present invention is illustrated by a compoundof Formula II:

or a pharmaceutically acceptable salt or stereoisomer thereof,wherein:

-   a is 0 or 1;-   b is 0 or 1;-   m is 0, 1, or 2;-   n is 0 or 1;-   r is 0 or 1;-   s is 0 or 1;-   X is selected from —CH₂— and —CH₂CH₂—;-   Y is selected from: O, N(R^(c)), S, —C(═O)—, —CH(R⁸)—,    —N(R^(c))C(═O)— and —N(R^(c))CH(R⁸)—;-   Z is selected from: —C(═O)—, —C(═S)—, —SO₂— and —C(R⁸)(R⁹)—,-   R¹ and R⁴ are independently selected from:

1) aryl,

2) C₁-C₆ aralkyl,

3) C₃-C₈ cycloalkyl, and

4) heterocyclyl,

-   said aryl, cycloalkyl, aralkyl and heterocyclyl is optionally    substituted with one or more substituents selected from R¹⁰;-   R² is selected from:

1) H,

2) C₁-C₁₀ alkyl,

3) aryl,

4) C₂-C₁₀ alkenyl,

5) C₂-C₁₀ alkynyl,

6) C₁-C₆ perfluoroalkyl,

7) C₁-C₆ aralkyl,

8) C₃-C₈ cycloalkyl, and

9) heterocyclyl,

-   said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, aralkyl and    heterocyclyl is optionally substituted with one or more substituents    selected from R¹⁰;-   R^(3a) and R⁵ are independently selected from:

1) H,

2) C₁-C₁₀ alkyl,

3) C₁-C₆ perfluoroalkyl,

4) C₁-C₆ aralkyl,

-   said alkyl and aralkyl is optionally substituted with one or more    substituents selected from R¹⁰;-   R⁸ and R⁹ is independently selected from:

1) H,

2) (C═O)_(a)O_(b)C₁-C₁₀ alkyl,

3) (C═O)_(a)O_(b)aryl,

4) (C═O)_(a)O_(b) heterocyclyl,

5) CO₂H,

6) halo,

7) CN,

8) OH,

9) O_(b)C₁-C₆ perfluoroalkyl,

10) O_(a)(C═O)_(b)NR¹²R¹³, and

11) (C═O)_(a)O_(b)C₃-C₈ cycloalkyl,

-   said alkyl, aryl, heterocyclyl, and cycloalkyl optionally    substituted with one or more substituents selected from R¹¹;-   R¹⁰ is independently selected from:

1) (C═O)_(a)O_(b)C₁-C₁₀ alkyl,

2) (C═O)_(a)O_(b)aryl,

3) C₂-C₁₀ alkenyl,

4) C₂-C₁₀ alkynyl,

5) (C═O)_(a)O_(b) heterocyclyl,

6) CO₂H,

7) halo,

8) CN,

9) OH,

10) O_(b)C₁-C₆ perfluoroalkyl,

11) O_(a)(C═O)_(b)NR¹²R¹³,

12) S(O)_(m)R^(a),

13) S(O)₂NR¹²R¹³,

14) oxo,

15) CHO,

16) (N═O)R¹²R¹³,

17) (C═O)_(a)O_(b)C₃-C₈ cycloalkyl, and

18) —OPO(OH)₂;

-   said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl    optionally substituted with one, two or three substituents selected    from R¹¹;-   R¹¹ is selected from:

1) (C═O)_(r)O_(s)(C₁-C₁₀)alkyl,

2) O_(r)(C₁-C₃)perfluoroalkyl,

3) oxo,

4) OH,

5) halo,

6) CN,

7) (C₂-C₁₀)alkenyl,

8) (C₂-C₁₀)alkynyl,

9) (C═O)_(r)O_(s)(C₃-C₆)cycloalkyl,

10) (C═O)_(r)O_(s)(C₀-C₆)alkylene-aryl,

11) (C═O)_(r)O_(s)(C₀-C₆)alkylene-heterocyclyl,

12) (C═O)_(r)O_(s)(C₀-C₆)alkylene-N(R^(b))₂,

13) C(O)R^(a),

14) (C₀-C₆)alkylene-CO₂R^(a),

15) C(O)H,

16) (C₀-C₆)alkylene-CO₂H, and

17) C(O)N(R^(b))₂,

18) S(O)_(m)R_(a),

19) S(O)₂N(R^(b))₂; and

20) —OPO(OH)₂;

-   said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylene and    heterocyclyl is optionally substituted with up to three substituents    selected from R^(b), OH, (C₁-C₆)alkoxy, halogen, CO₂H, CN,    O(C═O)C₁-C₆ alkyl, oxo, and N(R^(b))₂;-   R¹² and R¹³ are independently selected from:

1) H,

2) (C═O)O_(b)C₁-C₁₀ alkyl,

3) (C═O)O_(b)C₃-C₈ cycloalkyl,

4) (C═O)O_(b)aryl,

5) (C═O)O_(b)heterocyclyl,

6) C₁-C₁₀ alkyl,

7) aryl,

8) C₂-C₁₀ alkenyl,

9) C₂-C₁₀ alkynyl,

10) heterocyclyl,

11) C₃-C₈ cycloalkyl,

12) SO₂R^(a), and

13) (C═O)NR^(b) ₂,

-   said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl is    optionally substituted with one, two or three substituents selected    from R¹¹, or-   R¹² and R¹³ can be taken together with the nitrogen to which they    are attached to form a monocyclic or bicyclic heterocycle with 5-7    members in each ring and optionally containing, in addition to the    nitrogen, one or two additional heteroatoms selected from N, O and    S, said monocyclic or bicyclic heterocycle optionally substituted    with one, two or three substituents selected from R¹¹;-   R^(a) is (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, aryl, or heterocyclyl;-   R^(b) is H, (C₁-C₆)alkyl, aryl, heterocyclyl, (C₃-C₆)cycloalkyl,    (C═O)OC₁-C₆ alkyl, (C═O)C₁-C₆ alkyl or S(O)₂R^(a);-   R^(c) and R^(c′) are independently selected from: H, (C₁-C₆)alkyl,    aryl, heterocyclyl and (C₃-C₆)cycloalkyl; or-   R^(c) and R^(c′) can be taken together with the nitrogen to which    they are attached to form a monocyclic or bicyclic heterocycle with    5-7 members in each ring and optionally containing, in addition to    the nitrogen, one or two additional heteroatoms selected from N, O    and S, said monocyclic or bicyclic heterocycle optionally    substituted with one, two or three substituents selected from R¹¹;-   R^(d) and R^(d′) are independently selected from: (C₁-C₆)alkyl,    (C₁-C₆)alkoxy and NR^(b) ₂, or-   R^(d) and R^(d′) can be taken together with the phosphorous to which    they are attached to form a monocyclic heterocycle with 5-7 members    the ring and optionally containing, in addition to the phosphorous,    one or two additional heteroatoms selected from NR^(e), O and S,    said monocyclic heterocycle optionally substituted with one, two or    three substituents selected from R¹¹; and-   R^(e) is selected from: H and (C₁-C₆)alkyl.

Another embodiment of the present invention is illustrated by a compoundof Formula III:

or pharmaceutically acceptable salt or stereoisomer thereof,wherein:

-   a is 0 or 1;-   b is 0 or 1;-   m is 0, 1, or 2;-   n is 0 or 1;-   r is 0 or 1;-   s is 0 or 1;-   X is selected from —CH₂— and —CH₂CH₂—;-   Y is selected from: O, N(R^(c)), S, —C(═O)—, —CH(R⁸)—,    —N(R^(c))C(═O)— and —N(R^(c))CH(R⁸)—;-   Z is selected from: —C(═O)—, —C(═S)—, —SO₂— and —C(R⁸)(R⁹)—,-   R¹ and R⁴ are independently selected from:

1) aryl,

2) C₁-C₆ aralkyl,

3) C₃-C₈ cycloalkyl, and

4) heterocyclyl,

-   said aryl, cycloalkyl, aralkyl and heterocyclyl is optionally    substituted with one or more substituents selected from R¹⁰;-   R² is selected from:

1) H,

2) C₁-C₁₀ alkyl,

3) aryl,

4) C₂-C₁₀ alkenyl,

5) C₂-C₁₀ alkynyl,

6) C₁-C₆ perfluoroalkyl,

7) C₁-C₆ aralkyl,

8) C₃-C₈ cycloalkyl, and

9) heterocyclyl,

-   said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, aralkyl and    heterocyclyl is optionally substituted with one or more substituents    selected from R¹⁰;-   R^(3a) and R⁵ are independently selected from:

1) H,

2) C₁-C₁₀ alkyl,

3) C₁-C₆ perfluoroalkyl,

4) C₁-C₆ aralkyl,

-   said alkyl and aralkyl is optionally substituted with one or more    substituents selected from R¹⁰;-   R⁸ and R⁹ is independently selected from:

1) H,

2) (C═O)_(a)O_(b)C₁-C₁₀ alkyl,

3) (C═O)_(a)O_(b)aryl,

4) (C═O)_(a)O_(b) heterocyclyl,

5) CO₂H,

6) halo,

7) CN,

8) OH,

9) O_(b)C₁-C₆ perfluoroalkyl,

10) O_(a)(C═O)_(b)NR¹²R¹³, and

11) (C═O)_(a)O_(b)C₃-C₈ cycloalkyl,

-   said alkyl, aryl, heterocyclyl, and cycloalkyl optionally    substituted with one or more substituents selected from R¹¹;-   R¹⁰ is independently selected from:

1) (C═O)_(a)O_(b)C₁-C₁₀ alkyl,

2) (C═O)_(a)O_(b)aryl,

3) C₂-C₁₀ alkenyl,

4) C₂-C₁₀ alkynyl,

5) (C═O)_(a)O_(b) heterocyclyl,

6) CO₂H,

7) halo,

8) CN,

9) OH,

10) O_(b)C₁-C₆ perfluoroalkyl,

11) O_(a)(C═O)_(b)NR¹²R¹³,

12) S(O)_(m)R^(a),

13) S(O)₂NR¹²R¹³,

14) oxo,

15) CHO,

16) (N═O)R¹²R¹³,

17) (C═O)_(a)O_(b)C₃-C₈ cycloalkyl, and

18) —OPO(OH)₂;

-   said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl    optionally substituted with one, two or three substituents selected    from R¹¹;

R¹¹ is selected from:

1) (C═O)_(r)O_(s)(C₁-C₁₀)alkyl,

2) O_(r)(C₁-C₃)perfluoroalkyl,

3) oxo,

4) OH,

5) halo,

6) CN,

7) (C₂-C₁₀)alkenyl,

8) (C₂-C₁₀)alkynyl,

9) (C═O)_(r)O_(s)(C₃-C₆)cycloalkyl,

10) (C═O)_(r)O_(s)(C₀-C₆)alkylene-aryl,

11) (C═O)_(r)O_(s)(C₀-C₆)alkylene-heterocyclyl,

12) (C═O)_(r)O_(s)(C₀-C₆)alkylene-N(R^(b))₂,

13) C(O)R^(a),

14) (C₀-C₆)alkylene-CO₂R^(a),

15) C(O)H,

16) (C₀-C₆)alkylene-CO₂H, and

17) C(O)N(R^(b))₂,

18) S(O)_(m)R_(a),

19) S(O)₂N(R^(b))₂; and

20) —OPO(OH)₂;

-   said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylene and    heterocyclyl is optionally substituted with up to three substituents    selected from R^(b), OH, (C₁-C₆)alkoxy, halogen, CO₂H, CN,    O(C═O)C₁-C₆ alkyl, oxo, and N(R^(b))₂;-   R¹² and R¹³ are independently selected from:

1) H,

2) (C═O)O_(b)C₁-C₁₀ alkyl,

3) (C═O)O_(b)C₃-C₈ cycloalkyl,

4) (C═O)O_(b)aryl,

5) (C═O)O_(b)heterocyclyl,

6) C₁-C₁₀ alkyl,

7) aryl,

8) C₂-C₁₀ alkenyl,

9) C₂-C₁₀ alkynyl,

10) heterocyclyl,

11) C₃-C₈ cycloalkyl,

12) SO₂R^(a), and

13) (C═O)NR^(b) ₂,

-   said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl is    optionally substituted with one, two or three substituents selected    from R¹¹, or-   R¹² and R¹³ can be taken together with the nitrogen to which they    are attached to form a monocyclic or bicyclic heterocycle with 5-7    members in each ring and optionally containing, in addition to the    nitrogen, one or two additional heteroatoms selected from N, O and    S, said monocyclic or bicyclic heterocycle optionally substituted    with one, two or three substituents selected from R¹¹;-   R^(a) is (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, aryl, or heterocyclyl;-   R^(b) is H, (C₁-C₆)alkyl, aryl, heterocyclyl, (C₃-C₆)cycloalkyl,    (C═O)OC₁-C₆ alkyl, (C═O)C₁-C₆ alkyl or S(O)₂R^(a);-   R^(c) and R^(c′) are independently selected from: H, (C₁-C₆)alkyl,    aryl, heterocyclyl and (C₃-C₆)cycloalkyl; or-   R^(c) and R^(c′) can be taken together with the nitrogen to which    they are attached to form a monocyclic or bicyclic heterocycle with    5-7 members in each ring and optionally containing, in addition to    the nitrogen, one or two additional heteroatoms selected from N, O    and S, said monocyclic or bicyclic heterocycle optionally    substituted with one, two or three substituents selected from R¹¹;-   R^(d) and R^(d′) are independently selected from: (C₁-C₆)alkyl,    (C₁-C₆)alkoxy and NR^(b) ₂, or-   R^(d) and R^(d′) can be taken together with the phosphorous to which    they are attached to form a monocyclic heterocycle with 5-7 members    the ring and optionally containing, in addition to the phosphorous,    one or two additional heteroatoms selected from NR^(e), O and S,    said monocyclic heterocycle optionally substituted with one, two or    three substituents selected from R¹¹; and-   R^(e) is selected from: H and (C₁-C₆)alkyl.

A further embodiment of the present invention is illustrated by acompound of Formula IV:

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

-   a is 0 or 1;-   b is 0 or1;-   m is 0, 1, or 2;-   r is 0 or 1;-   s is 0 or 1;-   X is selected from —CH₂— and —CH₂CH₂—;-   Y is selected from: O, N(R^(c)) and —CH(R⁸)—;-   Z is selected from: —C(═O)—, —C(═S)—, —SO₂— and —C(R⁸)(R⁹)—,-   R¹ is selected from:

1) aryl,

2) C₁-C₆ aralkyl,

3) C₃-C₈ cycloalkyl, and

4) heterocyclyl,

-   said aryl, cycloalkyl, aralkyl and heterocyclyl is optionally    substituted with one or more substituents selected from R¹⁰;-   R² is selected from:

1) H,

2) C₁-C₁₀ alkyl,

3) aryl,

4) C₂-C₁₀ alkenyl,

5) C₂-C₁₀ alkynyl,

6) C₁-C₆ perfluoroalkyl,

7) C₁-C₆ aralkyl,

8) C₃-C₈ cycloalkyl, and

9) heterocyclyl,

-   said alkyl, aryl, alkenyl, aLkynyl, cycloalkyl, aralkyl and    heterocyclyl is optionally substituted with one or more substituents    selected from R¹⁰;-   R⁸ and R⁹ is independently selected from:

1) H,

2) (C═O)_(a)O_(b)C₁-C₁₀ alkyl,

3) CO₂H,

4) halo,

5) OH,

6) O_(a)(C═O)_(b)NR¹²R¹³, and

7) (C═O)_(a)O_(b)C₃-C₈ cycloalkyl,

-   said alkyl, aryl, heterocyclyl, and cycloalkyl optionally    substituted with one or more substituents selected from R¹¹;-   R¹⁰ is independently selected from:

1) (C═O)_(a)O_(b)C₁-C₁₀ alkyl,

2) (C═O)_(a)O_(b)aryl,

3) C₂-C₁₀ alkenyl,

4) C₂-C₁₀alkynyl,

5) (C═O)_(a)O_(b) heterocyclyl,

6) CO₂H,

7) halo,

8) CN,

9) OH,

10) O_(b)C₁-C₆ perfluoroalkyl,

11) O_(a)(C═O)_(b)NR¹²R¹³,

12) S(O)_(m)R^(a),

13) S(O)₂NR¹²R¹³,

14) oxo,

15) CHO,

16) (N═O)R¹²R¹³,

17) (C═O)_(a)O_(b)C₃-C₈ cycloalkyl, and

18) —OPO(OH)₂;

-   said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl    optionally substituted with one, two or three substituents selected    from R¹¹;-   R^(10′) is halogen;-   R¹¹ is selected from:

1) (C═O)_(r)O_(s)(C₁-C₁₀)alkyl,

2) O_(r)(C₁-C₃)perfluoroalkyl,

3) oxo,

4) OH,

5) halo,

6) CN,

7) (C₂-C₁₀)alkenyl,

8) (C₂-C₁₀)alkynyl,

9) (C═O)_(r)O_(s)(C₃-C₆)cycloalkyl,

10) (C═O)_(r)O_(s)(C₀-C₆)alkylene-aryl,

11) (C═O)_(r)O_(s)(C₀-C₆)alkylene-heterocyclyl,

12) (C═O)_(r)O_(s)(C₀-C₆)alkylene-N(R^(b))₂,

13) C(O)R^(a),

14) (C₀-C₆)alkylene-CO₂R^(a),

15) C(O)H,

16) (C₀-C₆)alkylene-CO₂H, and

17) C(O)N(R^(b))₂,

18) S(O)_(m)R^(a),

19) S(O)₂N(R^(b))₂; and

20) —OPO(OH)₂;

-   said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl is    optionally substituted with up to three substituents selected from    R^(b), OH, (C₁-C₆)alkoxy, halogen, CO₂H, CN, O(C═O)C₁-C₆ alkyl, oxo,    and N(R^(b))₂;-   R¹² and R¹³ are independently selected from:

1) H,

2) (C═O)O_(b)C₁-C₁₀ alkyl,

3) (C═O)O_(b)C₃-C₈ cycloalkyl,

4) (C═O)O_(b)aryl,

5) (C═O)O_(b)heterocyclyl,

6) C₁-C₁₀ alkyl,

7) aryl,

8) C₂-C₁₀ alkenyl,

9) C₂-C₁₀ alkynyl,

10) heterocyclyl,

11) C₃-C₈ cycloalkyl,

12) SO₂R^(a), and

13) (C═O)NR^(b) ₂,

-   said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl is    optionally substituted with one, two or three substituents selected    from R¹¹, or-   R¹² and R¹³ can be taken together with the nitrogen to which they    are attached to form a monocyclic or bicyclic heterocycle with 5-7    members in each ring and optionally containing, in addition to the    nitrogen, one or two additional heteroatoms selected from N, O and    S, said monocyclic or bicyclic heterocycle optionally substituted    with one, two or three substituents selected from R¹¹;-   R^(a) is (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, aryl, or heterocyclyl;-   R^(b) is H, (C₁-C₆)alkyl, aryl, heterocyclyl, (C₃-C₆)cycloalkyl,    (C═O)OC₁-C₆ alkyl, (C═O)C₁-C₆ alkyl or S(O)₂R^(a);-   R^(c) and R^(c′) are independently selected from: H, (C₁-C₆)alkyl,    aryl, heterocyclyl and (C₃-C₆)cycloalkyl; or-   R^(c) and R^(c′) can be taken together with the nitrogen to which    they are attached to form a monocyclic or bicyclic heterocycle with    5-7 members in each ring and optionally containing, in addition to    the nitrogen, one or two additional heteroatoms selected from N, O    and S, said monocyclic or bicyclic heterocycle optionally    substituted with one, two or three substituents selected from    R^(11;)-   R^(d) and R^(d′) are independently selected from: (C₁-C₆)alkyl,    (C₁-C₆)alkoxy and NR^(b) ₂, or-   R^(d) and R^(d′) can be taken together with the phosphorous to which    they are attached to form a monocyclic heterocycle with 5-7 members    the ring and optionally containing, in addition to the phosphorous,    one or two additional heteroatoms selected from NR^(e), O and S,    said monocyclic heterocycle optionally substituted with one, two or    three substituents selected from R¹¹; and-   R^(e) is selected from: H and (C₁-C₆)alkyl.

A further embodiment of the present invention is illustrated by acompound of Formula V:

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

-   a is 0 or 1;-   b is 0 or 1;-   m is 0, 1, or 2;-   r is 0 or 1;-   s is 0 or 1;-   X is selected from —CH₂— and —CH₂CH₂—;-   Y is selected from: O, N(R^(c)) and —CH(R⁸)—;-   Z is selected from: —C(═O)—, —C(═S)—, —SO₂— and —C(R⁸)(R⁹)—,-   R² is selected from:

1) H,

2) C₁-C₁₀ alkyl,

3) aryl,

4) C₂-C₁₀ alkenyl,

5) C₂-C₁₀ alkynyl,

6) C₁-C₆ perfluoroalkyl,

7) C₁-C₆ aralkyl,

8) C₃-C₈ cycloalkyl, and

9) heterocyclyl,

-   said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, aralkyl and    heterocyclyl is optionally substituted with one or more substituents    selected from R¹⁰;-   R⁸and R⁹is independently selected from:

1) H,

2) (C═O)_(a)O_(b)C₁-C₁₀ alkyl,

3) CO₂H,

4) halo,

5) OH,

6) O_(a)(C═O)_(b)NR¹²R¹³, and

7) (C═O)_(a)O_(b)C₃-C₈ cycloalkyl,

-   said alkyl, aryl, heterocyclyl, and cycloalkyl optionally    substituted with one or more substituents selected from R¹¹;-   R¹⁰ is independently selected from:

1) (C═O)_(a)O_(b)C₁-C₁₀ alkyl,

2) (C═O)_(a)O_(b)aryl,

3) C₂-C₁₀ alkenyl,

4) C₂-C₁₀ alkynyl,

5) (C═O)_(a)O_(b) heterocyclyl,

6) CO₂H,

7) halo,

8) CN,

9) OH,

10) O_(b)C₁-C₆ perfluoroalkyl,

11) O_(a)(C═O)_(b)NR¹²R¹³,

12) S(O)_(m)R^(a),

13) S(O)₂NR¹²R¹³,

14) oxo,

15) CHO,

16) (N═O)R¹²R¹³,

17) (C═O)_(a)O_(b)C₃-C₈ cycloalkyl, and

18) —OPO(OH)₂;

-   said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl    optionally substituted with one, two or three substituents selected    from R¹¹;-   R^(10′) is halogen;-   R¹¹ is selected from:

1) (C═O)_(r)O_(s)(C₁-C₁₀)alkyl,

2) O_(r)(C₁-C₃)Perfluoroalkyl,

3) oxo,

4) OH,

5) halo,

6) CN,

7) (C₂-C₁₀)alkenyl,

8) (C₂-C₁₀)alkynyl,

9) (C═O)_(r)O_(s)(C₃-C₆)cycloalkyl,

10) (C═O)_(r)O_(s)(C₀-C₆)alkylene-aryl,

11) (C═O)_(r)O_(s)(C₀-C₆)alkylene-heterocyclyl,

12) (C═O)_(r)O_(s)(C₀-C₆)alkylene-N(R^(b))₂,

13) C(O)R^(a),

14) (C₀-C₆)alkylene-CO₂R^(a),

15) C(O)H,

16) (C₀-C₆)alkylene-CO₂H, and

17) C(O)N(R^(b))₂,

18) S(O)_(m)R^(a),

19) S(O)₂N(R^(b))₂; and

20) —OPO(OH)²;

-   said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl is    optionally substituted with up to three substituents selected from    R^(b), OH, (C₁-C₆)alkoxy, halogen, CO₂H, CN, O(C═O)C₁-C₆ alkyl, oxo,    and N(R^(b))₂;-   R¹² and R¹³ are independently selected from:

1) H,

2) (C═O)O_(b)C₁-C₁₀ alkyl,

3) (C═O)O_(b)C₃-C₈ cycloalkyl,

4) (C═O)O_(b)aryl,

5) (C═O)O_(b)heterocyclyl,

6) C₁-C₁₀ alkyl,

7) aryl,

8) C₂-C₁₀ alkenyl,

9) C₂-C₁₀ alkynyl,

10) heterocyclyl,

11) C₃-C₈ cycloalkyl,

12) SO₂R^(a), and

13) (C═O)NR^(b) ₂,

-   said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl is    optionally substituted with one, two or three substituents selected    from R¹¹, or-   R¹² and R¹³ can be taken together with the nitrogen to which they    are attached to form a monocyclic or bicyclic heterocycle with 5-7    members in each ring and optionally containing, in addition to the    nitrogen, one or two additional heteroatoms selected from N, O and    S, said monocyclic or bicyclic heterocycle optionally substituted    with one, two or three substituents selected from R¹¹;-   R^(a) is (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, aryl, or heterocyclyl;-   R^(b) is H, (C₁-C₆)alkyl, aryl, heterocyclyl, (C₃-C₆)cycloalkyl,    (C═O)OC₁-C₆ alkyl, (C═O)C₁-C₆ alkyl or S(O)₂R^(a);-   R^(c) and R^(c′) are independently selected from: H, (C₁-C₆)alkyl,    aryl, heterocyclyl and (C₃-C₆)cycloalkyl; or-   R^(c) and R^(c′) can be taken together with the nitrogen to which    they are attached to form a monocyclic or bicyclic heterocycle with    5-7 members in each ring and optionally containing, in addition to    the nitrogen, one or two additional heteroatoms selected from N, O    and S, said monocyclic or bicyclic heterocycle optionally    substituted with one, two or three substituents selected from R¹¹;-   R^(d) and R^(d′) are independently selected from: (C₁-C₆)alkyl,    (C₁-C₆)alkoxy and NR^(b) ₂, or-   R^(d) and R^(d′) can be taken together with the phosphorous to which    they are attached to form a monocyclic heterocycle with 5-7 members    the ring and optionally containing, in addition to the phosphorous,    one or two additional heteroatoms selected from NR^(e), O and S,    said monocyclic heterocycle optionally substituted with one, two or    three substituents selected from R¹¹; and-   R^(e) is selected from: H and (C₁-C₆)alkyl.

Specific examples of the compounds of the instant invention include:

-   (−)-(5S,8aR)-7-(2,5-difluorophenyl)-5-phenyl-1,5,8,8a-tetrahydroindolizin-3(2H)-one    and-   (+)-(5S,8aR)-7-(2,5-difluorophenyl)-5-phenyl-1,5,6,8a-tetrahydroindolizin-3(2H)-one    or a pharmaceutically acceptable salt or stereoisomer thereof.

The compounds of the present invention may have asymmetric centers,chiral axes, and chiral planes (as described in: E. L. Eliel and S. H.Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York,1994, pages 1119-1190), and occur as racemates, racemic mixtures, and asindividual diastereomers, with all possible isomers and mixturesthereof, including optical isomers, all such stereoisomers beingincluded in the present invention. In addition, the compounds disclosedherein may exist as tautomers and both tautomeric forms are intended tobe encompassed by the scope of the invention, even though only onetautomeric structure is depicted.

When any variable (e.g. R¹⁰, R¹¹, R¹², etc.) occurs more than one timein any constituent, its definition on each occurrence is independent atevery other occurrence. Also, combinations of substituents and variablesare permissible only if such combinations result in stable compounds.lines drawn into the ring systems from substituents represent that theindicated bond may be attached to any of the substitutable ring atoms.If the ring system is polycyclic, it is intended that the bond beattached to any of the suitable carbon atoms on the proximal ring only.

It is understood that substituents and substitution patterns on thecompounds of the instant invention can be selected by one of ordinaryskill in the art to provide compounds that are chemically stable andthat can be readily synthesized by techniques known in the art, as wellas those methods set forth below, from readily available startingmaterials. If a substituent is itself substituted with more than onegroup, it is understood that these multiple groups may be on the samecarbon or on different carbons, so long as a stable structure results.The phrase “optionally substituted with one or more substituents” shouldbe taken to be equivalent to the phrase “optionally substituted with atleast one substituent” and in such cases the preferred embodiment willhave from zero to three substituents.

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms. For example, C₁-C₁₀, as in “C₁-C₁₀alkyl” is defined to include groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or10 carbons in a linear or branched arrangement. For example, “C₁-C₁₀alkyl” specifically includes methyl, ethyl, n-propyl, i-propyl, n-butyl,t-butyl, i-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and so on.The term “cycloalkyl” means a monocyclic saturated aliphatic hydrocarbongroup having the specified number of carbon atoms. For example,“cycloalkyl” includes cyclopropyl, methyl-cyclopropyl,2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, and so on. Inan embodiment of the invention the term “cycloalkyl” includes the groupsdescribed immediately above and further includes monocyclic unsaturatedaliphatic hydrocarbon groups. For example, “cycloalkyl” as defined inthis embodiment includes cyclopropyl, methyl-cyclopropyl,2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, cyclopentenyl,cyclobutenyl and so on.

The term “alkylene” means a hydrocarbon diradical group having thespecified number of carbon atoms. For example, “alkylene” includes—CH₂—, —CH₂CH₂— and the like.

When used in the phrases “C₁-C₆ aralkyl” and “C₁-C₆ heteroaralkyl” theterm “C₁-C₆” refers to the alkyl portion of the moiety and does notdescribe the number of atoms in the aryl and heteroaryl portion of themoiety.

“Alkoxy” represents either a cyclic or non-cyclic alkyl group ofindicated number of carbon atoms attached through an oxygen bridge.“Alkoxy” therefore encompasses the definitions of alkyl and cycloalkylabove.

If no number of carbon atoms is specified, the term “alkenyl” refers toa non-aromatic hydrocarbon radical, straight, branched or cyclic,containing from 2 to 10 carbon atoms and at least one carbon to carbondouble bond. Preferably one carbon to carbon double bond is present, andup to four non-aromatic carbon-carbon double bonds may be present. Thus,“C₂-C₆ alkenyl” means an alkenyl radical having from 2 to 6 carbonatoms. Alkenyl groups include ethenyl, propenyl, butenyl,2-methylbutenyl and cyclohexenyl. The straight, branched or cyclicportion of the alkenyl group may contain double bonds and may besubstituted if a substituted alkenyl group is indicated.

The term “alkynyl” refers to a hydrocarbon radical straight, branched orcyclic, containing from 2 to 10 carbon atoms and at least one carbon tocarbon triple bond. Up to three carbon-carbon triple bonds may bepresent. Thus, “C₂-C₆ alkynyl” means an alkynyl radical having from 2 to6 carbon atoms. Alkynyl groups include ethynyl, propynyl, butynyl,3-methylbutynyl and so on. The straight, branched or cyclic portion ofthe alkynyl group may contain triple bonds and may be substituted if asubstituted alkynyl group is indicated.

In certain instances, substituents may be defined with a range ofcarbons that includes zero, such as (C₀-C₆)alkylene-aryl. If aryl istaken to be phenyl, this definition would include phenyl itself as wellas —CH₂Ph, —CH₂CH₂Ph, CH(CH₃)CH₂CH(CH₃)Ph, and so on.

As used herein, “aryl” is intended to mean any stable monocyclic orbicyclic carbon ring of up to 7 atoms in each ring, wherein at least onering is aromatic. Examples of such aryl elements include phenyl,naphthyl, tetrahydronaphthyl, indanyl and biphenyl. In cases where thearyl substituent is bicyclic and one ring is non-aromatic, it isunderstood that attachment is via the aromatic ring.

The term heteroaryl, as used herein, represents a stable monocyclic orbicyclic ring of up to 7 atoms in each ring, wherein at least one ringis aromatic and contains from 1 to 4 heteroatoms selected from the groupconsisting of O, N and S. Heteroaryl groups within the scope of thisdefinition include but are not limited to: acridinyl, carbazolyl,cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, furanyl,thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl,oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl,pyrimidinyl, pyrrolyl, tetrahydroquinoline. As with the definition ofheterocycle below, “heteroaryl” is also understood to include theN-oxide derivative of any nitrogen-containing heteroaryl. In cases wherethe heteroaryl substituent is bicyclic and one ring is non-aromatic orcontains no heteroatoms, it is understood that attachment is via thearomatic ring or via the heteroatom containing ring, respectively.

The term “heterocycle” or “heterocyclyl” as used herein is intended tomean a 3- to 10-membered aromatic or nonaromatic heterocycle containingfrom 1 to 4 heteroatoms selected from the group consisting of O, N andS, and includes bicyclic groups. “Heterocyclyl” therefore includes theabove mentioned heteroaryls, as well as dihydro and tetrathydro analogsthereof. Further examples of “heterocyclyl” include, but are not limitedto the following: azetidinyl, benzoimidazolyl, benzofuranyl,benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl,benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl,indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl,isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl,oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl,pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl,tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydroisoquinolinyl,tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl,triazolyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl,pyridin-2-onyl, pyrrolidinyl, morpholinyl, thiomorpholinyl,dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl,dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl,dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl,dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, andN-oxides thereof. Attachment of a heterocyclyl substituent can occur viaa carbon atom or via a heteroatom.

In an embodiment, the term “heterocycle” or “heterocyclyl” as usedherein is intended to mean a 5- to 10-membered aromatic or nonaromaticheterocycle containing from 1 to 4 heteroatoms selected from the groupconsisting of O, N and S, and includes bicyclic groups. “Heterocyclyl”in this embodiment therefore includes the above mentioned heteroaryls,as well as dihydro and tetrathydro analogs thereof. Further examples of“heterocyclyl” include, but are not limited to the following:benzoirnidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl,benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl,cinnolinyl, furanyl, irnidazolyl, indolinyl, indolyl, indolazinyl,indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl,isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline,isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl,quinazolinyl, quinolyl, quinoxalinyl, tetrahydropyranyl,tetrahydrothiopyranyl, tetrahydroisoquinolinyl, tetrazolyl,tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl,azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl,pyridin-2-onyl, pyrrolidinyl, morpholinyl, thiomorpholinyl,dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl,dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl,dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl,dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, andN-oxides thereof. Attachment of a heterocyclyl substituent can occur viaa carbon atom or via a heteroatom.

In another embodiment, heterocycle is selected from 2-azepinone,benzimidazolyl, 2-diazapinone, imidazolyl, 2-imidazolidinone, indolyl,isoquinolinyl, morpholinyl, piperidyl, piperazinyl, pyridyl,pyrrolidinyl, 2-piperidinone, 2-pyrimidinone, 2-pyrollidinone,quinolinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, and thienyl.

As appreciated by those of skill in the art, “halo” or “halogen” as usedherein is intended to include chloro, fluoro, bromo and iodo.

The alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl andheterocyclyl substituents may be substituted or unsubstituted, unlessspecifically defined otherwise. For example, a (C₁-C₆)alkyl may besubstituted with one, two or three substituents selected from OH, oxo,halogen, alkoxy, dialkylamino, or heterocyclyl, such as morpholinyl,piperidinyl, and so on. In this case, if one substituent is oxo and theother is OH, the following are included in the definition:

-   —C═O)CH₂CH(OH)CH₃, —(C═O)OH, —CH₂(OH)CH₂CH(O), and so on.

The moiety illustrated by the formula:

includes the following structures, which are meant to be merelyillustrative and not limiting. The substituents on the ring atoms (suchas R⁸ and R^(c)) are shown as H to simplify the structures and are notmeant to be limiting.

The moiety formed when, in the definition of R^(3a) and R^(3b) and R⁵and R⁶ on the same carbon atom are combined to form —(CH₂)_(u)— isillustrated by the following:

In addition, such cyclic moieties may optionally include aheteroatom(s). Examples of such heteroatom-containing cyclic moietiesinclude, but are not limited to:

In certain instances, R¹² and R¹³ and R^(c) and R^(c′) are defmed suchthat they can be taken together with the nitrogen to which they areattached to form a monocyclic or bicyclic heterocycle with 5-7 membersin each ring and optionally containing, in addition to the nitrogen, oneor two additional heteroatoms selected from N, O and S, said heterocycleoptionally substituted with one or more substituents selected from R¹¹.Examples of the heterocycles that can thus be formed include, but arenot limited to the following, keeping in mind that the heterocycle isoptionally substituted with one or more (and preferably one, two orthree) substituents chosen from R¹¹:

In certain instances, R^(d) and R^(d′) are defined such that they can betaken together with the phosphorous to which they are attached to form amonocyclic heterocycle with 5-7 members in the ring and optionallycontaining, in addition to the nitrogen, one or two additionalheteroatoms selected from NR^(e), O and S, said heterocycle optionallysubstituted with one or more substituents selected from R¹¹. Examples ofthe heterocycles that can thus be formed include, but are not limited tothe following, keeping in mind that the heterocycle is optionallysubstituted with one or more (and preferably one or two) substituentschosen from R¹¹:

In an embodiment R¹ is selected from aryl, optionally substituted withone to three substituents selected from R¹⁰. In a further embodiment, R¹is phenyl, optionally substituted with one to three substituentsselected from halo and OH.

In embodiment, R^(3a), R^(3b), R⁶ and R⁷ are H and R⁵. is absent and adouble bond is present between the carbon attached to R⁴ and the carbonattached to R⁶.

In another embodiment, R^(3a), R⁵, R⁶ and R⁷ are H and R^(3b) is absentand a double bond is present between the carbon attached to R⁴ and thecarbon attached to R^(3a).

In an embodiment R² is selected from H and C₁-C₆ alkyl, optionallysubstituted with one to two substituents selected from R¹⁰.

In an embodiment R⁴ is selected from aryl, optionally substituted withone to three substituents selected from R¹⁰. In a further embodiment, R⁴is phenyl, optionally substituted with one to three substituentsselected from halo.

In an embodiment, X is selected from —CH₂— and —CH₂CH₂—.

In an embodiment, Y is selected from: O, N(R^(c)) and —CH(R⁸)—.

In an embodiment, Z is selected from: —C(═O)—, —C(═S)—, —SO₂— and—C(R⁸)(R⁹)—.

Included in the instant invention is the free form of compounds ofFormula I, as well as the pharmaceutically acceptable salts andstereoisomers thereof. Some of the specific compounds exemplified hereinare the protonated salts of amine compounds. The term “free form” refersto the amine compounds in non-salt form. The encompassedpharmaceutically acceptable salts not only include the salts exemplifiedfor the specific compounds described herein, but also all the typicalpharmaceutically acceptable salts of the free form of compounds ofFormula I. The free form of the specific salt compounds described may beisolated using techniques known in the art. For example, the free formmay be regenerated by treating the salt with a suitable dilute aqueousbase solution such as dilute aqueous NaOH, potassium carbonate, ammoniaand sodium bicarbonate. The free forms may differ from their respectivesalt forms somewhat in certain physical properties, such as solubilityin polar solvents, but the acid and base salts are otherwisepharmaceutically equivalent to their respective free forms for purposesof the invention.

The pharmaceutically acceptable salts of the instant compounds can besynthesized from the compounds of this invention which contain a basicor acidic moiety by conventional chemical methods. Generally, the saltsof the basic compounds are prepared either by ion exchangechromatography or by reacting the free base with stoichiometric amountsor with an excess of the desired salt-forming inorganic or organic acidin a suitable solvent or various combinations of solvents. Similarly,the salts of the acidic compounds are formed by reactions with theappropriate inorganic or organic base.

Thus, pharmaceutically acceptable salts of the compounds of thisinvention include the conventional non-toxic salts of the compounds ofthis invention as formed by reacting a basic instant compound with aninorganic or organic acid. For example, conventional non-toxic saltsinclude those derived from inorganic acids such as hydrochloric,hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like, aswell as salts prepared from organic acids such as acetic, propionic,succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic,pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic,salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic,methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroaceticand the like.

When the compound of the present invention is acidic, suitable:“pharmaceutically acceptable salts” refers to salts prepared formpharmaceutically acceptable non-toxic bases including inorganic basesand organic bases. Salts derived from inorganic bases include aluminum,ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganicsalts, manganous, potassium, sodium, zinc and the like. Particularlypreferred are the ammonium, calcium, magnesium, potassium and sodiumsalts. Salts derived from pharmaceutically acceptable organic non-toxicbases include salts of primary, secondary and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as arginine, betainecaffeine, choline, N,N¹-dibenzylethylenediamine, diethylamin,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylaminetripropylamine, tromethamine and the like. When the compound of thepresent invention is acidic, the term “free form” refers to the compoundin its non-salt form, such that the acidic functionality is stillprotonated.

The preparation of the pharmaceutically acceptable salts described aboveand other typical pharmaceutically acceptable salts is more fullydescribed by Berg et al., “Pharmaceutical Salts,” J. Pharm. Sci.,1977:66:1-19.

It will also be noted that the compounds of the present invention maypotentially be internal salts or zwitterions, since under physiologicalconditions a deprotonated acidic moiety in the compound, such as acarboxyl group, may be anionic, and this electronic charge might then bebalanced off internally against the cationic charge of a protonated oralkylated basic moiety, such as a quaternary nitrogen atom. An isolatedcompound having internally balance charges and thus not associated witha intermolecular counterion, may also be considered the “free form” of acompound.

The compounds of this invention may be prepared by employing reactionsas shown in the following schemes, in addition to other standardmanipulations that are known in the literature or exemplified in theexperimental procedures. The illustrative schemes below, therefore, arenot limited by the compounds listed or by any particular substituentsemployed for illustrative purposes. Substituent numbering as shown inthe schemes does not necessarily correlate to that used in the claimsand often, for clarity, a single substituent is shown attached to thecompound where multiple substituents are allowed under the definitionsof Formula I hereinabove.

Schemes

As shown in Scheme A, the piperdone A-2, which is substituted with asuitably substituted phenyl group, is converted to a mixture of thecorresponding enol triflates A-3 and A-4. The triflates may then bereacted with a suitably substituted phenyl boraonic acid to provide thecompounds of the instant invention A-5 and A-6. Separation of the doublebond regioisomers and the mixtures of enantiomers and diastereomers maybe accomplished by silica and chiral chromatography at several pointsduring the synthetic scheme.

As shown in Scheme B, the lactazm ring of the bicyclic instant compoundsmay be further substituted.

Scheme C illustrates the preparation of the instant compounds having acarbamate moiety incorporated into the fused ring. Thus, deprotection ofthe benzyloxymethyl-2,3-dihydropyridinone C-1 (described in Comins, D.L. et al., J. Org. Chem. 2001, 66:6829-6832), followed by reaction withformic acid, provides the intermediate C-2. Compound C-2 may thenundergo reaction with a suitably substituted phenyl Grignard reagent,followed by conversion of the ketone moiety to the enol triflate.Subsequent reaction with a suitably substituted phenyl bonronic acidprovides the instant compound C4.

As illustrated in Scheme D, the carbamate functionality may behydrolytically cleaved to provide intermediate D-1. The hydroxyl moietymay then be converted to an amine. Subsequent deprotection of the ringnitrogen and reaction with triphosgene provides the instant compoundincorporating a urea function in the ring. Scheme D further illustratesN-substitution reactions and conversion of the urea functionality to athourea functionality.

Scheme E shows oxidation of intermediate D-1 to the correspondingcarboxylic acid E-1, which can undergo cyclization with a suitablysubstituted isocyanate to provide the instant dioxodiaza compound E-2.

Scheme F illustrates deprotection and sulfuryl chloride cyclization ofthe aminomethyl intermediate D-2 to provide the instant compound F-1.

Schemes G, H and I illustrate preparation of the fused [6.6] homologcompounds of the compounds described in Schemes C, D and F.

Utilities

The compounds of the invention find use in a variety of applications. Aswill be appreciated by those skilled in the art, mitosis may be alteredin a variety of ways; that is, one can affect mitosis either byincreasing or decreasing the activity of a component in the mitoticpathway. Stated differently, mitosis may be affected (e.g., disrupted)by disturbing equilibrium, either by inhibiting or activating certaincomponents. Similar approaches may be used to alter meiosis.

In a preferred embodiment, the compounds of the invention are used tomodulate mitotic spindle formation, thus causing prolonged cell cyclearrest in mitosis. By “modulate” herein is meant altering mitoticspindle formation, including increasing and decreasing spindleformation. By “mitotic spindle formation” herein is meant organizationof microtubules into bipolar structures by mitotic kinesins. By “mitoticspindle dysfunction” herein is meant mitotic arrest and monopolarspindle formation.

The compounds of the invention are useful to bind to and/or modulate theactivity of a mitotic kinesin. In a preferred embodiment, the mitotickinesin is a member of the bimC subfamily of mitotic kinesins (asdescribed in U.S. Pat. No. 6,284,480, column 5). In a further preferredembodiment, the mitotic kinesin is human KSP, although the activity ofmitotic kinesins from other organisms may also be modulated by thecompounds of the present invention. In this context, modulate meanseither increasing or decreasing spindle pole separation, causingmalformation, i.e., splaying, of mitotic spindle poles, or otherwisecausing morphological perturbation of the mitotic spindle. Also includedwithin the definition of KSP for these purposes are variants and/orfragments of KSP. In addition, other mitotic kinesins may be inhibitedby the compounds of the present invention.

The compounds of the invention are used to treat cellular proliferationdiseases. Disease states which can be treated by the methods andcompositions provided herein include, but are not limited to, cancer(further discussed below), autoimmune disease, arthritis, graftrejection, inflammatory bowel disease, proliferation induced aftermedical procedures, including, but not limited to, surgery, angioplasty,and the like. It is appreciated that in some cases the cells may not bein a hyper- or hypoproliferation state (abnormal state) and stillrequire treatment. For example, during wound healing, the cells may beproliferating “normally”, but proliferation enhancement may be desired.Similarly, as discussed above, in the agriculture arena, cells may be ina “normal” state, but proliferation modulation may be desired to enhancea crop by directly enhancing growth of a crop, or by inhibiting thegrowth of a plant or organism which adversely affects the crop. Thus, inone embodiment, the invention herein includes application to cells orindividuals afflicted or impending affliction with any one of thesedisorders or states.

The compounds, compositions and methods provided herein are particularlydeemed useful for the treatment of cancer including solid tumors such asskin, breast, brain, cervical carcinomas, testicular carcinomas, etc.More particularly, cancers that may be treated by the compounds,compositions and methods of the invention include, but are not limitedto: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma,liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung:bronchogenic carcinoma (squamous cell, undifferentiated small cell,undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar)carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatoushamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cellcarcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach(carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma,insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), smallbowel (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma,leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel(adenocarcinoma, tubular adenoma, villous adenoma, hamartoma,leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor[nephroblastoma], lymphoma, leukemia), bladder and urethra (squamouscell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate(adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonalcarcinoma, tefatocarcinoma, choriocarcinoma, sarcoma, interstitial cellcarcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver:hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma,angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenicsarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma and giant celltumors; Nervous svstem: skull (osteoma, hemangioma, granuloma, xanthoma,osteitis deformans), meninges (meningioma, meningiosarcoma,gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma,germinoma [pinealoma], glioblastoma multiform, oligodendroglioma,schwannoma, retinoblastoma, congenital tumors), spinal cordneurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus(endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervicaldysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma,mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecalcell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignantteratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma,adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma,squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma),fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia [acuteand chronic], acute lymphoblastic leukemia, chronic lymphocyticleukemia, myeloproliferative diseases, multiple myeloma, myelodysplasticsyndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignantlymphoma]; Skin: malignant melanoma, basal cell carcinoma, squamous cellcarcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma,dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma.Thus, the term “cancerous cell” as provided herein, includes a cellafflicted by any one of the above-identified conditions.

The compounds of the instant invention may also be useful as antifungalagents, by modulating the activity of the fungal members of the bimCkinesin subgroup, as is described in U.S. Pat. No. 6,284,480.

The compounds of this invention may be administered to mammals,preferably humans, either alone or, preferably, in combination withpharmaceutically acceptable carriers, excipients or diluents, in apharmaceutical composition, according to standard pharmaceuticalpractice. The compounds can be administered orally or parenterally,including the intravenous, intramuscular, intraperitoneal, subcutaneous,rectal and topical routes of administration.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specific amounts, aswell as any product which results, directly or indirectly, fromcombination of the specific ingredients in the specified amounts.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, microcrystalline cellulose, sodiumcrosscarmellose, corn starch, or alginic acid; binding agents, forexample starch, gelatin, polyvinyl-pyrrolidone or acacia, andlubricating agents, for example, magnesium stearate, stearic acid ortalc. The tablets may be uncoated or they may be coated by knowntechniques to mask the unpleasant taste of the drug or delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a watersoluble taste masking material such as hydroxypropyl-methylcellulose orhydroxypropylcellulose, or a time delay material such as.ethylcellulose, cellulose acetate butyrate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with watersoluble carrier such as polyethyleneglycol or an oil medium, for examplepeanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present. These compositions may be preserved by theaddition of an anti-oxidant such as ascorbic acid.

The pharmaceutical compositions of the invention may also be in the formof an oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally occurring phosphatides, for example soy bean lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening, flavoring agents, preservatives and antioxidants.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative, flavoring and coloring agentsand antioxidant.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous solutions. Among the acceptable vehicles and solventsthat may be employed are water, Ringer's solution and isotonic sodiumchloride solution.

The sterile injectable preparation may also be a sterile injectableoil-in-water microemulsion where the active ingredient is dissolved inthe oily phase. For example, the active ingredient may be firstdissolved in a mixture of soybean oil and lecithin. The oil solutionthen introduced into a water and glycerol mixture and processed to forma microemulation.

The injectable solutions or microemulsions may be introduced into apatient's blood stream by local bolus injection. Alternatively, it maybe advantageous to administer the solution or microemulsion in such away as to maintain a constant circulating concentration of the instantcompound. In order to maintain such a constant concentration, acontinuous intravenous delivery device may be utilized. An example ofsuch a device is the Deltec CADD-PLUS™ model 5400 intravenous pump.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension for intramuscular andsubcutaneous administration. This suspension may be formulated accordingto the known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally acceptable diluent or solvent,for example as a solution in 1,3-butane diol. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium. For this purpose any bland fixed oil may be employed includingsynthetic mono- or diglycerides. In addition, fatty acids such as oleicacid find use in the preparation of injectables.

Compounds of Formula I may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials include cocoa butter, glycerinated gelatin,hydrogenated vegetable oils, mixtures of polyethylene glycols of variousmolecular weights and fatty acid esters of polyethylene glycol.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compound of Formula I are employed. (For purposesof this application, topical application shall include mouth washes andgargles.)

The compounds for the present invention can be administered inintranasal form via topical use of suitable intranasal vehicles anddelivery devices, or via transdermal routes, using those forms oftransdermal skin patches well known to those of ordinary skill in theart. To be administered in the form of a transdermal delivery system,the dosage administration will, of course, be continuous rather thanintermittent throughout the dosage regimen. Compounds of the presentinvention may also be delivered as a suppository employing bases such ascocoa butter, glycerinated gelatin, hydrogenated vegetable oils,mixtures of polyethylene glycols of various molecular weights and fattyacid esters of polyethylene glycol.

When a compound according to this invention is administered into a humansubject, the daily dosage will normally be determined by the prescribingphysician with the dosage generally varying according to the age,weight, sex and response of the individual patient, as well as theseverity of the patient's symptoms.

In one exemplary application, a suitable amount of compound isadministered to a mammal undergoing treatment for cancer. Administrationoccurs in an amount between about 0.1 mg/kg of body weight to about 60mg/kg of body weight per day, preferably of between 0.5 mg/kg of bodyweight to about 40 mg/kg of body weight per day.

The instant compounds are also useful in combination with knowntherapeutic agents and anti-cancer agents. For example, instantcompounds are useful in combination with known anti-cancer agents.Combinations of the presently disclosed compounds with other anti-canceror chemotherapeutic agents are within the scope of the invention.Examples of such agents can be found in Cancer Principles and Practiceof Oncology by V. T. Devita and S. Hellman (editors), 6^(th) edition(Feb. 15, 2001), Lippincott Williams & Wilkins Publishers. A person ofordinary skill in the art would be able to discern which combinations ofagents would be useful based on the particular characteristics of thedrugs and the cancer involved. Such anti-cancer agents include, but arenot limited to, the following: estrogen receptor modulators, androgenreceptor modulators, retinoid receptor modulators, cytotoxic/cytostaticagents, antiproliferative agents, prenyl-protein transferase inhibitors,HMG-CoA reductase inhibitors and other angiogenesis inhibitors,inhibitors of cell proliferation and survival signaling, apoptosisinducing agents and agents that interfere with cell cycle checkpoints.The instant compounds are particularly useful when co-administered withradiation therapy.

In an embodiment, the instant compounds are also useful in combinationwith known anti-cancer agents including the following: estrogen receptormodulators, androgen receptor modulators, retinoid receptor modulators,cytotoxic agents, antiproliferative agents, prenyl-protein transferaseinhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors,reverse transcriptase inhibitors, and other angiogenesis inhibitors.

“Estrogen receptor modulators” refers to compounds that interfere withor inhibit the binding of estrogen to the receptor, regardless ofmechanism. Examples of estrogen receptor modulators include, but are notlimited to, tamoxifen, raloxifene, idoxifene, LY353381, LY117081,toremifene, fulvestrant,4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]-phenyl-2,2-methylpropanoate,4,4′-dihydroxybenzophenone-2,4dinitrophenyl-hydrazone, and SH646.

“Androgen receptor modulators” refers to compounds which interfere orinhibit the binding of androgens to the receptor, regardless ofmechanism. Examples of androgen receptor modulators include finasterideand other 5α-reductase inhibitors, nilutamide, flutamide, bicalutamide,liarozole, and abiraterone acetate.

“Retinoid receptor modulators” refers to compounds which interfere orinhibit the binding of retinoids to the receptor, regardless ofmechanism. Examples of such retinoid receptor modulators includebexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid,α-difluoromethylornithine, ILX23-7553, trans-N-(4′-hydroxyphenyl)retinamide, and N-4-carboxyphenyl retinamide.

“Cytotoxic/cytostatic agents” refer to compounds which cause cell deathor inhibit cell proliferation primarily by interfering directly with thecell's functioning or inhibit or interfere with cell myosis, includingalkylating agents, tumor necrosis factors, intercalators, hypoxiaactivatable compounds, microtubule inhibitors/microtubule-stabilizingagents, inhibitors of mitotic kinesins, inhibitors of kinases involvedin mitotic progression, antimetabolites; biological response modifiers;hormonal/anti-hormonal therapeutic agents, haematopoietic growthfactors, monoclonal antibody targeted therapeutic agents, topoisomeraseinhibitors, proteosome inhibitors and ubiquitin ligase inhibitors.

Examples of cytotoxic agents include, but are not limited to, sertenef,cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, altretamine,prednimustine, dibromodulcitol, ranimustine, fotemustine, nedaplatin,oxaliplatin, temozolomide, heptaplatin, estramustine, improsulfantosilate, trofosfamide, nimustine, dibrospidium chloride, pumitepa,lobaplatin, satraplatin, profiromycin, cisplatin, irofulven,dexifosfamide, cis-aminedichloro(2-methyl-pyridine)platinum,benzylguanine, glufosfamide, GPX100, (trans, trans,trans)-bis-mu-(hexane-1,6-diamine)-mu-[diamine-platinum(II)]bis[diamine(chloro)platinum(II)]tetrachloride, diarizidinylspermine, arsenic trioxide,1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine, zorubicin,idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin,pinafide, valrubicin, amrubicin, antineoplaston,3′-deamino-3′-morpholino-13-deoxo-10-hydroxycarminomycin, annamycin,galarubicin, elinafide, MEN10755, and4-demethoxy-3-deamino-3-aziridinyl-4-methylsulphonyl-daunorubicin (seeWO 00/50032).

An example of a hypoxia activatable compound is tirapazamine.

Examples of proteosome inhibitors include but are not limited tolactacystin and MLN-341 (Velcade).

Examples of microtubule inhibitors/microtubule-stabilising agentsinclude paclitaxel, vindesine sulfate,3′,4′-didehydro-4′-deoxy-8′-norvincaleukoblastine, docetaxol, rhizoxin,dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR109881,BMS184476, vinflunine, cryptophycin,2,3,4,5,6-pentafluoro-N-(3-fluoro4-methoxyphenyl)benzene sulfonamide,anhydrovinblastine,N,N-dimethyl-L-valyl-L-valyl-N-methyl-Lvalyl-L-prolyl-L-proline-t-butylamide,TDX258, the epothilones (see for example U.S. Pat. Nos. 6,284,781 and6,288,237) and BMS188797. In an embodiment the epothilones are notincluded in the microtubule inhibitors/microtubule-stabilising agents.

Some examples of topoisomerase inhibitors are topotecan, hycaptamine,irinotecan, rubitecan,6-ethoxypropionyl-3′,4′-O-exo-benzylidene-chartreusin,9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H)propanamine,1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3′,4′:b,7]-indolizino[1,2b]quinoline-10,13(9H,15H)dione,lurtotecan, 7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin, BNP1350,BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane,2′-dimethylamino-2′-deoxy-etoposide, GL331,N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide,asulacrine, (5a, 5aB,8aa,9b)-9-[2-[N-[2-(dimethylamino)ethyl]-N-methylamino]ethyl]-5-[4-hydrooxy-3,5-dimethoxyphenyl]-5,5a,6,8,8a,9-hexohydrofuro(3′,4′:6,7)naphtho(2,3-d)-1,3-dioxol-6-one,2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]-phenanthridinium,6,9-bis[(2-aminoethyl)amino]benzo[g]isoguinoline-5,10-dione,5-(3-aminopropylamino)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5,1-de]acridin-6-one,N-[1-[2(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl]formamide,N-(2-(dimethylamino)ethyl)acridine-4-carboxamide,6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one, and dimesna.

Examples of inhibitors of mitotic kinesins, and in particular the humanmitotic kinesin KSP, are described in PCT Publications WO 01/30768 andWO 01/98278, WO 03/050,064 (Jun. 19, 2003), WO 03/050,122 (Jun. 19,2003), WO 03/049,527 (Jun. 19, 2003), WO 03/049,679 (Jun. 19, 2003), WO03/049,678 (Jun. 19, 2003) and WO 03/39460 (May 15, 2003) and pendingPCT Appl. Nos. US03/06403 (filed Mar. 4, 2003), US03/15861 (filed May19, 2003), US03/15810 (filed May 19, 2003), US03/18482 (filed Jun. 12,2003) and US03/18694 (filed Jun. 12, 2003 In an embodiment inhibitors ofmitotic kinesins include, but are not limited to inhibitors of KSP,inhibitors of MKLP1, inhibitors of CENP-E, inhibitors of MCAK,inhibitors of Kif14, inhibitors of Mphosph1 and inhibitors of Rab6-KIFL.

“inhibitors of kinases involved in mitotic progression” include, but arenot limited to, inhibitors of aurora kinase, inhibitors of Polo-likekinases (PLK) (in particular inhibitors of PLK-1), inhibitors of bub-1and inhibitors of bub-R1.

“Antiproliferative agents” includes antisense RNA and DNAoligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001,and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin,doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine,cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed,paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed,nelzarabine, 2′-deoxy-2′-methylidenecytidine,2′-fluoromethylene-2′-deoxycytidine,N-[5-(2,3-dihydro-benzofuryl)sulfonyl]-N′-(3,4-dichlorophenyl)urea,N6-[4-deoxy-4-[N2-[2(E),4(E)-tetradecadienoyl]glycylamino]-L-glycero-B-L-manno-heptopyranosyl]adenine,aplidine, ecteinascidin, troxacitabine,4-[2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4-b][1,4]thiazin-6-yl-(S)-ethyl]-2,5-thienoyl-L-glutamicacid, aminopterin, 5-flurouracil, alanosine,11-acetyl-8-(carbamoyloxymethyl)-4-formyl-6-methoxy-14-oxa-1,11-diazatetracyclo(7.4.1.0.0)-tetradeca-2,4,6-trien-9-ylacetic acid ester, swainsonine, lometrexol, dexrazoxane, methioninase,2′-cyano-2′-deoxy-N4-palmitoyl-1-B-D-arabino furanosyl cytosine and3-aminopyridine-2-carboxaldehyde thiosemicarbazone.

Examples of monoclonal antibody targeted therapeutic agents includethose therapeutic agents which have cytotoxic agents or radioisotopesattached to a cancer cell specific or target cell specific monoclonalantibody. Examples include Bexxar.

“HMG-CoA reductase inhibitors” refers to inhibitors of3-hydroxy-3-methylglutaryl-CoA reductase. Compounds which haveinhibitory activity for HMG-CoA reductase can be readily identified byusing assays well-known in the art. For example, see the assaysdescribed or cited in U.S. Pat. No. 4,231,938 at col. 6, and WO 84/02131at pp. 30-33. The terms “MG-CoA reductase inhibitor” and “inhibitor ofHMG-CoA reductase” have the same meaning when used herein.

Examples of HMG-CoA reductase inhibitors that may be used include butare not limited to lovastatin (MEVACOR®; see U.S. Pat. Nos. 4,231,938,4,294,926 and 4,319,039), simvastatin (ZOCOR®; see U.S. Pat. Nos.4,444,784, 4,820,850 and 4,916,239), pravastatin (PRAVACHOL®; see U.S.Pat. Nos. 4,346,227, 4,537,859, 4,410,629, 5,030,447 and 5,180,589),fluvastatin (LESCOL®; see U.S. Pat. Nos. 5,354,772, 4,911,165,4,929,437, 5,189,164, 5,118,853, 5,290,946 and 5,356,896), atorvastatin(LPITOR®; see U.S. Pat. Nos. 5,273,995, 4,681,893, 5,489,691 and5,342,952) and cerivastatin (also known as rivastatin and BAYCHOL®; seeU.S. Pat. No. 5,177,080). The structural formulas of these andadditional HMG-CoA reductase inhibitors that may be used in the instantmethods are described at page 87 of M. Yalpani, “Cholesterol LoweringDrugs”, Chemistry & Industry, pp. 85-89 (5 Feb. 1996) and U.S. Pat. Nos.4,782,084 and 4,885,314. The term HMG-CoA reductase inhibitor as usedherein includes all pharmaceutically acceptable lactone and open-acidforms (i.e., where the lactone ring is opened to form the free acid) aswell as salt and ester forms of compounds which have HMG-CoA reductaseinhibitory activity, and therefor the use of such salts, esters,open-acid and lactone forms is included within the scope of thisinvention. An illustration of the lactone portion and its correspondingopen-acid form is shown below as structures I and II.

In HMG-CoA reductase inhibitors where an open-acid form can exist, saltand ester forms may be formed from the open-acid, and all such forms areincluded within the meaning of the term “HMG-COA reductase inhibitor” asused herein. In an embodiment, the HMG-COA reductase inhibitor isselected from lovastatin and simvastatin, and in a further embodiment,simvastatin. Herein, the term “pharmaceutically acceptable salts” withrespect to the HMG-COA reductase inhibitor shall mean non-toxic salts ofthe compounds employed in this invention which are generally prepared byreacting the free acid with a suitable organic or inorganic base,particularly those formed from cations such as sodium, potassium,aluminum, calcium, lithium, magnesium, zinc and tetramethylammonium, aswell as those salts formed from amines such as ammonia, ethylenediamine,N-methylglucamine, lysine, arginine, ornithine, choline,N,N′-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine,N-benzylphenethylamine,1-p-chlorobenzyl-2-pyrrolidine-1′-yl-methylbenz-imidazole, diethylamine,piperazine, and tris(hydroxymethyl) aminomethane. Further examples ofsalt forms of HMG-CoA reductase inhibitors may include, but are notlimited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate,bitartrate, borate, bromide, calcium edetate, camsylate, carbonate,chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate,estolate, esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynapthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamaote,palmitate, panthothenate, phosphate/diphosphate, polygalacturonate,salicylate, stearate, subacetate, succinate, tannate, tartrate,teoclate, tosylate, triethiodide, and valerate.

Ester derivatives of the described HMG-CoA reductase inhibitor compoundsmay act as prodrugs which, when absorbed into the bloodstream of awarm-blooded animal, may cleave in such a manner as to release the drugform and permit the drug to afford improved therapeutic efficacy.

“Prenyl-protein transferase inhibitor” refers to a compound whichinhibits any one or any combination of the prenyl-protein transferaseenzymes, including farnesyl-protein transferase (FPTase),geranylgeranyl-protein transferase type I (GGPTase-I), andgeranylgeranyl-protein transferase type-II (GGPTase-II, also called RabGGPTase). Examples of prenyl-protein transferase inhibiting compoundsinclude(±)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone,(−)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone,(+)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone,5(S)-n-butyl-1-(2,3-dimethylphenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone,(S)-1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl)methyl)-2-piperazinone,5(S)-n-Butyl-1-(2-methylphenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone,1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-2-methyl-5-imidazolylmethyl]-2-piperazinone,1-(2,2-diphenylethyl)-3-[N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl]piperidine,4-{5-[4-hydroxymethyl-4-(4-chloropyridin-2-ylmethyl)-piperidine-1-ylmethyl]-2-methylimidazol-1-ylmethyl}benzonitrile,4-{5-[4-hydroxymethyl-4-(3-chlorobenzyl)-piperidine-1-ylmethyl]-2-methylimidazol-1-ylmethyl)benzonitrile,4-{3-[4-(2-oxo-2H-pyridin-1-yl)benzyl]-3H-imidazol-4-ylmethyl)benzonitrile,4-{3-[4-(5-chloro-2-oxo-2H-[1,2′]bipyridin-5′-ylmethyl]-3H-imidazol-4-ylmethyl}benzonitrile,4-{3-[4-(2-oxo-2H-[1,2′]bipyridin-5′-ylmethyl]-3H-imidazol-4-ylmethyl}benzonitrile,4-[3-(2-oxo-1-phenyl-1,2-dihydropyridin-4-ylmethyl)-3H-imidazol-4-ylmethyl}benzonitrile,18,19-dihydro-19-oxo-5H,17H-6,10:12,16-dimetheno-1H-imidazo[4,3-c][1,11,4]dioxaazacyclo-nonadecine-9-carbonitrile,(±)-19,20-dihydro-19-oxo-5H-18,21-ethano-12,14-etheno-6,10-metheno-22H-benzo[d]imidazo[4,3-k][1,6,9,12]oxatriaza-cyclooctadecine-9-carbonitrile,19,20-dihydro-19-oxo-5H,17H-18,21-ethano-6,10:12,16-dimetheno-22H-imidazo[3,4-h][1,8,11,14]oxatriazacycloeicosine-9-carbonitrile,and(±)-19,20-dihydro-3-methyl-19-oxo-5H-18,21-ethano-12,14-etheno-6,10-metheno-22H-benzo[d]imidazo[4,3-k][1,6,9,12]oxa-triazacyclooctadecine-9-carbonitrile.

Other examples of prenyl-protein transferase inhibitors can be found inthe following publications and patents: WO 96/30343, WO 97/18813, WO97/21701, WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO95/32987, U.S. Pat. No. 5,420,245, U.S. Pat. No. 5,523,430, U.S. Pat.No. 5,532,359, U.S. Pat. No. 5,510,510, U.S. Pat. No. 5,589,485, U.S.Pat. No. 5,602,098, European Patent Publ. 0 618 221, European PatentPubl. 0 675 112, European Patent Publ. 0 604 181, European Patent Publ.0 696 593, WO 94/19357, WO 95/08542, WO 95/11917, WO 95/12612, WO95/12572, WO 95/10514, U.S. Pat. No. 5,661,152, WO 95/10515, WO95/10516, WO 95/24612, WO 95/34535, WO 95/25086, WO 96/05529, WO.96/06138, WO 96/06193, WO 96/16443, WO 96/21701, WO 96/21456, WO96/22278, WO 96/24611, WO 96/24612, WO 96/05168, WO 96/05169, WO96/00736, U.S. Pat. No. 5,571,792, WO 96/17861, WO 96/33159, WO96/34850, WO 96/34851, WO 96/30017, WO 96/30018, WO 96/30362, WO96/30363, WO 96/31111, WO 96/31477, WO 96/31478, WO 96/31501, WO97/00252, WO 97/03047, WO 97/03050, WO 97/04785, WO 97/02920, WO97/17070, WO 97/23478, WO 97/26246, WO 97/30053, WO 97/44350, WO98/02436, and U.S. Pat. No. 5,532,359.

For an example of the role of a prenyl-protein transferase inhibitor onangiogenesis see European J. of Cancer, Vol. 35, No. 9, pp. 1394-1401(1999).

“Angiogenesis inhibitors” refers to compounds that inhibit the formationof new blood vessels, regardless of mechanism. Examples of angiogenesisinhibitors include, but are not limited to, tyrosine kinase inhibitors,such as inhibitors of the tyrosine kinase receptors Flt-1 (VEGFR1) andFlk-1/KDR (VEGFR2), inhibitors of epidermal-derived, fibroblast-derived,or platelet derived growth factors, MMP (matrix metalloprotease)inhibitors, integrin blockers, interferon-α, interleukin-12,pentosan.polysulfate, cyclooxygenase inhibitors, including nonsteroidalanti-inflammatories (NSAIDs) like aspirin and ibuprofen as well asselective cyclooxy-genase-2 inhibitors like celecoxib and rofecoxib(PNAS, Vol. 89, p. 7384 (1992); JNCI, Vol. 69, p. 475 (1982); Arch.Opthalmol., Vol. 108, p. 573 (1990); Anat. Rec., Vol. 238, p. 68 (1994);FEBS Letters, Vol. 372, p. 83 (1995); Clin, Orthop. Vol. 313, p. 76(1995); J. Mol. Endocrinol., Vol. 16, p. 107 (1996); Jpn. J. Pharmacol.,Vol. 75, p. 105 (1997); Cancer Res., Vol. 57, p. 1625 (1997); Cell, Vol.93, p. 705 (1998); Intl. J. Mol. Med., Vol. 2, p. 715 (1998); J. Biol.Chem., Vol. 274, p. 9116 (1999)), steroidal anti-inflammatories (such ascorticosteroids, mineralocorticoids, dexamethasone, prednisone,prednisolone, methylpred, betamethasone), carboxyamidotriazole,combretastatin A-4, squalamine, 6-O-chloroacetyl-carbonyl)-fumagillol,thalidomide, angiostatin, troponin-1, angiotensin II antagonists (seeFernandez et al., J. Lab. Clin. Med. 105:141-145 (1985)), and antibodiesto VEGF (see, Nature Biotechnology, Vol. 17, pp. 963-968 (October 1999);Kim et al., Nature, 362, 841-844 (1993); WO 00/44777; and WO 00/61186).

Other therapeutic agents that modulate or inhibit angiogenesis and mayalso be used in combination with the compounds of the instant inventioninclude agents that modulate or inhibit the coagulation and fibrinolysissystems (see review in Clin. Chem. La Med. 38:679-692 (2000)). Examplesof such agents that modulate. or inhibit the coagulation andfibrinolysis pathways include, but are not limited to, heparin (seeThromb. Haemost. 80:10-23 (1998)), low molecular weight heparins andcarboxypeptidase U inhibitors (also known as inhibitors of activethrombin activatable fibrinolysis inhibitor [TAFIa) (see Thrombosis Res.101:329-354 (2001)). TAFIa inhibitors have been described in PCTPublication WO 03/013,526 and U.S. Ser. No. 60/349,925 (filed Jan. 18,2002).

“Agents that interfere with cell cycle checkpoints” refer to compoundsthat inhibit protein kinases that transduce cell cycle checkpointsignals, thereby sensitizing the cancer cell to DNA damaging agents.Such agents include inhibitors of ATR, ATM, the Chk1 and Chk2 kinasesand cdk and cdc kinase inhibitors and are specifically exemplified by7-hydroxystaurosporin, flavopiridol, CYC202 (Cyclacel) and BMS-387032.

“Inhibitors of cell proliferation and survival signaling pathway” referto pharmaceutical agents that inhibit cell surface receptors and signaltransduction cascades downstream of those surface receptors. Such agentsinclude inhibitors of inhibitors of EGFR (for example gefitinib anderlotinib), inhibitors of ERB-2 (for example trastuzumab), inhibitors ofIGFR, inhibitors of cytokine receptors, inhibitors of MET, inhibitors ofPI3K (for example LY294002), serine/threonine kinases (including but notlimited to inhibitors of Akt such as described in WO 02/083064, WO02/083139, WO 02/083140 and WO 02/083138), inhibitors of Raf kinase (forexample BAY-43-9006 ), inhibitors of MEK (for example CI-1040 andPD-098059) and inhibitors of mTOR (for example Wyeth CCI-779). Suchagents include small molecule inhibitor compounds and antibodyantagonists.

“Apoptosis inducing agents” include activators of TNF receptor familymembers (including the TRAIL receptors).

The combinations with NSAID's are directed to the use of NSAID's whichare potent COX-2 inhibiting agents. For purposes of this specificationan NSAD is potent if it possesses an IC₅₀ for the inhibition of COX-2 of1 μM or less as measured by cell or microsomal assays.

The invention also encompasses combinations with NSAID's which areselective COX-2 inhibitors. For purposes of this specification NSAID'swhich are selective inhibitors of COX-2 are defined as those whichpossess a specificity for inhibiting COX-2 over COX-1 of at least 100fold as measured by the ratio of IC₅₀ for COX-2 over IC₅₀ for COX-1evaluated by cell or microsomal assays. Such compounds include, but arenot limited to those disclosed in U.S. Pat. No. 5,474,995, issued Dec.12, 1995, U.S. Pat. No. 5,861,419, issued Jan. 19, 1999, U.S. Pat. No.6,001,843, issued Dec. 14, 1999, U.S. Pat. No. 6,020,343, issued Feb. 1,2000, U.S. Pat. No. 5,409,944, issued Apr. 25, 1995, U.S. Pat. No.5,436,265, issued Jul. 25, 1995, U.S. Pat. No. 5,536,752, issued Jul.16, 1996, U.S. Pat. No. 5,550,142, issued Aug. 27, 1996, U.S. Pat. No.5,604,260, issued Feb. 18, 1997, U.S. Pat. No. 5,698,584, issued Dec.16, 1997, U.S. Pat. No. 5,710,140, issued Jan. 20,1998, WO 94/15932,published Jul. 21, 1994, U.S. Pat. No. 5,344,991, issued Jun. 6, 1994,U.S. Pat. No. 5,134,142, issued Jul. 28, 1992, U.S. Pat. No. 5,380,738,issued Jan. 10, 1995, U.S. Pat. No. 5,393,790, issued Feb. 20, 1995,U.S. Pat. No. 5,466,823, issued Nov. 14, 1995, U.S. Pat. No. 5,633,272,issued May 27, 1997, and U.S. Pat. No. 5,932,598, issued Aug. 3, 1999,all of which are hereby incorporated by reference.

Inhibitors of COX-2 that are particularly useful in the instant methodof treatment are:

3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone; and

5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine;

or a pharmaceutically acceptable salt thereof.

General and specific synthetic procedures for the preparation of theCOX-2 inhibitor compounds described above are found in U.S. Pat. No.5,474,995, issued Dec. 12, 1995, U.S. Pat. No. 5,861,419, issued Jan.19, 1999, and U.S. Pat. No. 6,001,843, issued Dec. 14, 1999, all ofwhich are herein incorporated by reference.

Compounds that have been described as specific inhibitors of COX-2 andare therefore useful in the present invention include, but are notlimited to, the following:

or a pharmaceutically acceptable salt thereof.

Compounds which are described as specific inhibitors of COX-2 and aretherefore useful in the present invention, and methods of synthesisthereof, can be found in the following patents, pending applications andpublications, which are herein incorporated by reference: WO 94/15932,published Jul. 21, 1994, U.S. Pat. No. 5,344,991, issued Jun. 6, 1994,U.S. Pat. No. 5,134,142, issued Jul. 28, 1992, U.S. Pat. No. 5,380,738,issued Jan. 10, 1995, U.S. Pat. No. 5,393,790, issued Feb. 20, 1995,U.S. Pat. No. 5,466,823, issued Nov. 14, 1995, U.S. Pat. No. 5,633,272,issued May 27, 1997, and U.S. Pat. No. 5,932,598, issued Aug. 3, 1999.

Compounds which are specific inhibitors of COX-2 and are thereforeuseful in the present invention, and methods of synthesis thereof, canbe found in the following patents, pending applications andpublications, which are herein incorporated by reference: U.S. Pat. No.5,474,995, issued Dec. 12, 1995, U.S. Pat. No. 5,861,419, issued Jan.19, 1999, U.S. Pat. No. 6,001,843, issued Dec. 14, 1999, U.S. Pat. No.6,020,343, issued Feb. 1, 2000, U.S. Pat. No. 5,409,944, issued Apr. 25,1995, U.S. Pat. No. 5,436,265, issued Jul. 25, 1995, U.S. Pat. No.5,536,752, issued Jul. 16, 1996, U.S. Pat. No. 5,550,142, issued Aug.27, 1996, U.S. Pat. No. 5,604,260, issued Feb. 18, 1997, U.S. Pat. No.5,698,584, issued Dec. 16, 1997, and U.S. Pat. No. 5,710,140, issuedJan. 20, 1998.

Other examples of angiogenesis inhibitors include, but are not limitedto, endostatin, ukrain, ranpirnase, IM862,5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]oct-6-yl(chloroacetyl)carbamate,acetyldinanaline,5-amino-1-[[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]methyl]-1H-1,2,3-triazole-4-carboxamide,CM101,squalamine, combretastatin, RPI4610, NX31838, sulfated mannopentaosephosphate,7,7-(carbonyl-bis[imino-N-methyl-4,2-pyrrolocarbonylimino[N-methyl-4,2-pyrrole]-carbonylimino]-bis-(1,3-naphthalenedisulfonate), and 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone(SU5416).

As used above, “integrin blockers” refers to compounds which selectivelyantagonize, inhibit or counteract binding of a physiological ligand tothe α_(v)β₃ integrin, to compounds which selectively antagonize, inhibitor counteract binding of a physiological ligand to the α_(v)β5 integrin,to compounds which antagonize, inhibit or counteract binding of aphysiological ligand to both the α_(v)β₃ integrin and the α_(v)β₅integrin, and to compounds which antagonize, inhibit or counteract theactivity of the particular integrin(s) expressed on capillaryendothelial cells. The term also refers to antagonists of the α_(v)β₆,α_(v)β₈, α₁β₁, α₂β₁, α₅β₁, α₆β₁ and α₆β₄ integrins. The term also refersto antagonists of any combination of α_(v)β₃, α_(v)β₅, α_(v)β₆, α_(v)β₈,α₁β₁, α₂β₁, α₅β₁, α₆β₁ and α₆β₄ integrins.

Some specific examples of tyrosine kinase inhibitors includeN-(trifluoromethylphenyl)-5-methylisoxazol-4-carboxamide,3-[(2,4-dimethylpyrrol-5-yl)methylidenyl)indolin-2-one,17-(allylamino)-17-demethoxygeldanamycin,4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-[3-(4-morpholinyl)prpoxyl]quinazoine,N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine,BIBX1382,2,3,9,10,11,12-hexahydro-10-(hydroxymethyl)-10-hydroxy-9-methyl-9,12-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-kl]pyrrolo[3,4-i[1,6]benzodiazocin-1-one,SH268, genistein, STI571, CEP2563,4-(3-chlorophenylamino)-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidinemethanesulfonate, 4-(3-bromo-4-hydroxyphenyl)amino-6,7-dimethoxyquinazoline,4-(4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, SU6668, STI571A,N-4-chlorophenyl-4-(4-pyridylmethyl)-1-phthalazinamine, and EMD121974.

Combinations with compounds other than anti-cancer compounds are alsoencompassed in the instant methods. For example, combinations of theinstantly claimed compounds with PPAR-γ (i.e., PPAR-gamma) agonists andPPAR-δ (i.e., PPAR-delta) agonists are useful in the treatment ofcertain malingnancies. PPAR-γ and PPAR-δ are the nuclear peroxisomeproliferator-activated receptors γ and δ. The expression of PPAR-γ onendothelial cells and its involvement in angiogenesis has been reportedin the literature (see J. Cardiovasc. Pharmacol. 1998; 31:909-913; J.Biol. Chem. 1999;274:9116-9121; Invest. Ophthalmol Vis. Sci. 2000;41:2309-2317). More recently, PPAR-γ agonists have been shown to inhibitthe angiogenic response to VEGF in vitro; both troglitazone androsiglitazone maleate inhibit the development of retinalneovascularization in mice. (Arch. Ophtlzanol. 2001; 119:709-717).Examples of PPAR-γ agonists and PPAR-γ/α agonists include, but are notlimited to, thiazolidinediones (such as DRF2725, CS-011, troglitazone,rosiglitazone, and pioglitazone), fenofibrate, gemfibrozil, clofibrate,GW2570, SB219994, AR-H039242, JTI-501, MCC-555, GW2331, GW409544,NN2344, KRP297, NPO110, DRF4158, NN622, G1262570, PNU182716, DRF552926,2-[(5,7-dipropyl-3-trifluoromethyl-1,2-benzisoxazol-6-yl)oxy]-2-methylpropionicacid (disclosed in U.S. Ser. No. 09/782,856), and2(R)-7-(3-(2-chloro-4-(4-fluorophenoxy)phenoxy)propoxy)-2-ethylchromane-2-carboxylic acid (disclosed in U.S.Ser. Nos. 60/235,708 and 60/244,697).

Another embodiment of the instant invention is the use of the presentlydisclosed compounds in combination with gene therapy for the treatmentof cancer. For an overview of genetic strategies to treating cancer seeHall et al (Am J Hum Genet 61:785-789, 1997) and Kufe et al (CancerMedicine, 5th Ed, pp 876-889, B C Decker, Hamilton 2000). Gene therapycan be used to deliver any tumor suppressing gene. Examples of suchgenes include, but are not limited to, p53, which can be delivered viarecombinant virus-mediated gene transfer (see U.S. Pat. No. 6,069,134,for example), a uPA/uPAR antagonist (“Adenovirus-Mediated Delivery of auPA/uPAR Antagonist Suppresses Angiogenesis-Dependent Tumor Growth andDissemination in Mice,” Gene Therapy, August 1998;5(8):1105-13), andinterferon gamma (J Immunol 2000;164:217-222).

The compounds of the instant invention may also be administered incombination with an inhibitor of inherent multidrug resistance (MDR), inparticular MDR associated with high levels of expression of transporterproteins. Such MDR inhibitors include inhibitors of p-glycoprotein(P-gp), such as LY335979, XR9576, OC144-093, R101922, VX853 and PSC833(valspodar).

A compound of the present invention may be employed in conjunction withanti-emetic agents to treat nausea or emesis, including acute, delayed,late-phase, and anticipatory emesis, which may result from the use of acompound of the present invention, alone or with radiation therapy. Forthe prevention or treatment of emesis, a compound of the presentinvention may be used in conjunction with other anti-emetic agents,especially neurokinin-1 receptor antagonists, 5HT3 receptor antagonists,such as ondansetron, granisetron, tropisetron, and zatisetron, GABABreceptor agonists, such as baclofen, a corticosteroid such as Decadron(dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten orothers such as disclosed in U.S. Pat. Nos. 2,789,118, 2,990,401,3,048,581, 3,126,375, 3,929,768, 3,996,359, 3,928,326 and 3,749,712, anantidopaminergic, such as the phenothiazines (for exampleprochlorperazine, fluphenazine, thioridazine and mesoridazine),metoclopramide or dronabinol. For the treatment or prevention of emesisthat may result upon administration of the instant compounds,conjunctive therapy with an anti-emesis agent selected from aneurokinin-1 receptor antagonist, a 5HT3 receptor antagonist and acorticosteroid is preferred.

Neurokinin-1 receptor antagonists of use in conjunction with thecompounds of the present invention are fully described, for example, inU.S. Pat. Nos. 5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595,5,459,270, 5,494,926, 5,496,833, 5,637,699, 5,719,147; European PatentPublication Nos. EP 0 360 390, 0 394 989, 0 428 434, 0 429 366, 0 430771, 0 436 334, 0 443 132, 0 482 539, 0 498 069, 0 499 313, 0 512 901, 0512 902, 0 514 273, 0 514 274, 0 514 275, 0 514 276, 0 515 681, 0 517589, 0 520 555, 0 522 808, 0 528 495, 0 532 456, 0 533 280, 0 536 817, 0545 478, 0 558 156, 0 577 394, 0 585 913,0 590 152, 0 599 538, 0 610793, 0 634 402, 0 686 629, 0 693 489, 0 694 535, 0 699 655, 0 699 674, 0707 006, 0 708 101, 0 709 375, 0 709 376, 0 714 891, 0 723 959, 0 733632 and 0 776 893; PCT International Patent Publication Nos. WO90/05525, 90/05729, 91/09844, 91/18899, 92/01688, 92/06079, 92/12151,92/15585, 92/17449, 92/20661, 92/20676, 92/21677, 92/22569, 93/00330,93/00331, 93/01159, 93/01165, 93/01169, 93/01170, 93/06099, 93/09116,93/10073, 93/14084, 93/14113, 93/18023, 93/19064, 93/21155, 93/21181,93/23380, 93/24465, 94/00440, 94/01402, 94/02461, 94/02595, 94/03429,94/03445, 94/04494, 94/04496, 94/05625, 94/07843, 94/08997, 94/10165,94/10167, 94/10168, 94/10170, 94/11368, 94/13639, 94/13663, 94/14767,94/15903, 94/19320, 94/19323, 94/20500, 94/26735, 94/26740, 94/29309,95/02595, 95/04040, 95/04042, 95/06645, 95/07886, 95/07908, 95/08549,95/11880, 95/14017, 95/15311, 95/16679, 95/17382, 95/18124, 95/18129,95/19344, 95/20575, 95/21819, 95/22525, 95/23798, 95126338, 95/28418,95/30674, 95/30687, 95/33744, 96/05181, 96/05193, 96/05203, 96/06094,96/07649, 96/10562, 96/16939, 96/18643, 96/20197, 96/21661, 96/29304,96/29317, 96/29326, 96/29328, 96/31214, 96/32385, 96/37489, 97/01553,97/01554, 97/03066, 97/08144, 97/14671, 97/17362, 97/18206, 97/19084,97/19942 and 97/21702; and in British Patent Publication Nos. 2 266 529,2 268 931, 2 269 170, 2 269 590, 2 271 774, 2 292 144, 2 293 168, 2 293169, and 2 302 689. The preparation of such compounds is fully describedin the aforementioned patents and publications, which are incorporatedherein by reference.

In an embodiment, the neurokinin-1 receptor antagonist for use inconjunction with the compounds of the present invention is selectedfrom:2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine,or a pharmaceutically acceptable salt thereof, which is described inU.S. Pat. No. 5,719,147.

A compound of the instant invention may also be administered with anagent useful in the treatment of anemia. Such an anemia treatment agentis, for example, a continuous eythropoiesis receptor activator (such asepoetin alfa).

A compound of the instant invention may also be administered with anagent useful in the treatment of neutropenia. Such a neutropeniatreatment agent is, for example, a hematopoietic growth factor whichregulates the production and function of neutrophils such as a humangranulocyte colony stimulating factor, (G-CSF). Examples of a G-CSFinclude filgrastim.

A compound of the instant invention may also be administered with animmunologic-enhancing drug, such as levamisole, isoprinosine andZadaxin.

Thus, the scope of the instant invention encompasses the use of theinstantly claimed compounds in combination with a second compoundselected from:

1) an estrogen receptor modulator,

2) an androgen receptor modulator,

3) retinoid receptor modulator,

4) a cytotoxic/cytostatic agent,

5) an antiproliferative agent,

6) a prenyl-protein transferase inhibitor,

7) an HMG-CoA reductase inhibitor,

8) an HIV protease inhibitor,

9) a reverse transcriptase inhibitor,

10) an angiogenesis inhibitor,

11) a PPAR-γ agonists,

12) a PPAR-δ agonists,

13) an inhibitor of inherent multidrug resistance,

14) an anti-emetic agent,

15) an agent useful in the treatment of anemia,

16) an agent useful in the treatment of neutropenia,

17) an immunologic-enhancing drug,

18) an inhibitor of cell proliferation and survival signaling,

19) an agent that interfers with a cell cycle checkpoint, and

20) an apoptosis inducing agent.

The term “administration” and variants thereof (e.g., “administering” acompound) in reference to a compound of the invention means introducingthe compound or a prodrug of the compound into the system of the animalin need of treatment. When a compound of the invention or prodrugthereof is provided in combination with one or more other active agents(e.g., a cytotoxic agent, etc.), “administration” and its variants areeach understood to include concurrent and sequential introduction of thecompound or prodrug thereof and other agents.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

The term “therapeutically effective amount” as used herein means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician.

The term “treating cancer” or “treatment of cancer” refers toadministration to a mammal afflicted with a cancerous condition andrefers to an effect that alleviates the cancerous condition by killingthe cancerous cells, but also to an effect that results in theinhibition of growth and/or metastasis of the cancer.

In an embodiment, the angiogenesis inhibitor to be used as the secondcompound is selected from a tyrosine kinase inhibitor, an inhibitor ofepidermal-derived growth factor, an inhibitor of fibroblast-derivedgrowth factor, an inhibitor of platelet derived growth factor, an MMP(matrix metalloprotease) inhibitor, an integrin blocker, interferon-α,interleukin-12, pentosan polysulfate, a cyclooxygenase inhibitor,carboxyamidotriazole, combretastatin A-4, squalamine,6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin,troponin-1, or an antibody to VEGF. In an embodiment, the estrogenreceptor modulator is tamoxifen or raloxifene.

Also included in the scope of the claims is a method of treating cancerthat comprises administering a therapeutically effective amount of acompound of Formula I in combination with radiation therapy and/or incombination with a compound selected from:

1) an estrogen receptor modulator,

2) an androgen receptor modulator,

3) a retinoid receptor modulator,

4) a cytotoxic/cytostatic agent,

5) an antiproliferative agent,

6) a prenyl-protein transferase inhibitor,

7) an HMG-CoA reductase inhibitor,

8) an HIV protease inhibitor,

9) a reverse transcriptase inhibitor,

10) an angiogenesis inhibitor,

11) PPAR-γ agonists,

12) PPAR-δ agonists,

13) an inhibitor of inherent multidrug resistance,

14) an anti-emetic agent,

15) an agent useful in the treatment of anemia,

16) an agent useful in the treatment of neutropenia,

17) an immunologic-enhancing drug,

18) an inhibitor of cell proliferation and survival signaling,

5 19) an agent that interfers with a cell cycle checkpoint, and

20) an apoptosis inducing agent.

And yet another embodiment of the invention is a method of treatingcancer that comprises administering a therapeutically effective amountof a compound of Formula I in combination with paclitaxel ortrastuzumab.

The invention further encompasses a method of treating or preventingcancer that comprises administering a therapeutically effective amountof a compound of -Formula I in combination with a COX-2 inhibitor.

The instant invention also includes a pharmaceutical composition usefulfor treating or preventing cancer that comprises a therapeuticallyeffective amount of a compound of Formula I and a compound selectedfrom:

1) an estrogen receptor modulator,

2) an androgen receptor modulator,

3) a retinoid receptor modulator,

4) a cytotoxic/cytostatic agent,

5) an antiproliferative agent,

6) a prenyl-protein transferase inhibitor,

7) an HMG-CoA reductase inhibitor,

8) an HIV protease inhibitor,

9) a reverse transcriptase inhibitor,

10) an angiogenesis inhibitor, and

11) a PPAR-γ agonist,

12) a PPAR-δ agonists;

13) an inhibitor of cell proliferation and survival signaling,

14) an agent that interfers with a cell cycle checkpoint, and

15) an apoptosis inducing agent.

The invention further comprises the use of the instant compounds in amethod to screen for other compounds that bind to KSP. To employ thecompounds of the invention in a method of screening for compounds thatbind to KSP kinesin, the KSP is bound to a support, and a compound ofthe invention (which is a mitotic agent) is added to the assay.Alternatively, the compound of the invention is bound to the support andKSP is added. Classes of compounds among which novel binding agents maybe sought include specific antibodies, non-natural binding agentsidentified in screens of chemical libraries, peptide analogs, etc. Ofparticular interest are screening assays for candidate agents that havea low toxicity for human cells. A wide variety of assays may be used forthis purpose, including labeled in vitro protein-protein binding assays,electrophoretic mobility shift assays, immunoassays for protein binding,functional assays (phosphorylation assays, etc.) and the like.

The determination of the binding of the mitotic agent to KSP may be donein a number of ways. In a preferred embodiment, the mitotic agent (thecompound of the invention) is labeled, for example, with a fluorescentor radioactive moiety and binding determined directly. For example, thismay be done by attaching all or a portion of KSP to a solid support,adding a labeled mitotic agent (for example a compound of the inventionin which at least one atom has been replaced by a detectable isotope),washing off excess reagent, and determining whether the amount of thelabel is that present on the solid support. Various blocking and washingsteps may be utilized as is known in the art.

By “labeled” herein is meant that the compound is either directly orindirectly labeled with a label which provides a detectable signal,e.g., radioisotope, fluorescent tag, enzyme, antibodies, particles suchas magnetic particles, chemiluminescent tag, or specific bindingmolecules, etc. Specific binding molecules include pairs, such as biotinand streptavidin, digoxin and antidigoxin etc. For the specific-bindingmembers, the complementary member would normally be labeled with amolecule which provides for detection, in accordance with knownprocedures, as outlined above. The label can directly or indirectlyprovide a detectable signal.

In some embodiments, only one of the components is labeled. For example,the kinesin proteins may be labeled at tyrosine positions using ¹²⁵I, orwith fluorophores. Alternatively, more than one component may be labeledwith different labels; using ¹²⁵I for the proteins, for example, and afluorophor for the mitotic agents.

The compounds of the invention may also be used as competitors to screenfor additional drug candidates. “Candidate bioactive agent” or “drugcandidate” or grammatical equivalents as used herein describe anymolecule, e.g., protein, oligopeptide, small organic molecule,polysaccharide, polynucleotide, etc., to be tested for bioactivity. Theymay be capable of directly or indirectly altering the cellularproliferation phenotype or the expression of a cellular proliferationsequence, including both nucleic acid sequences and protein sequences.In other cases, alteration of cellular proliferation protein bindingand/or activity is screened. Screens of this sort may be performedeither in the presence or absence of microtubules. In the case whereprotein binding or activity is screened, preferred embodiments excludemolecules already known to bind to that particular protein, for example,polymer structures such as microtubules, and energy sources such as ATP.Preferred embodiments of assays herein include candidate agents which donot bind the cellular proliferation protein in its endogenous nativestate termed herein as “exogenous” agents. In another preferredembodiment, exogenous agents further exclude antibodies to KSP.

Candidate agents can encompass numerous chemical classes, thoughtypically they are organic molecules, preferably small organic compoundshaving a molecular weight of more than 100 and less than about 2,500daltons. Candidate agents comprise functional groups necessary forstructural interaction with proteins, particularly hydrogen bonding andlipophilic binding, and typically include at least an amine, carbonyl,hydroxyl, ether, or carboxyl group, preferably at least two of thefunctional chemical groups. The candidate agents often comprise cyclicalcarbon or heterocyclic structures and/or aromatic or polyaromaticstructures substituted with one or more of the above functional groups.Candidate agents are also found among biomolecules including peptides,saccharides, fatty acids, steroids, purines, pyrimidines, derivatives,structural analogs or combinations thereof. Particularly preferred arepeptides.

Candidate agents are obtained from a wide variety of sources includinglibraries of synthetic or natural compounds. For example, numerous meansare available for random and directed synthesis of a wide variety oforganic compounds and biomolecules, including expression of randomizedoligonucleotides. Alternatively, libraries of natural compounds in theform of bacterial, fungal, plant and animal extracts are available orreadily produced. Additionally, natural or synthetically producedlibraries and compounds are readily modified through conventionalchemical, physical and biochemical means. Known pharmacological agentsmay be subjected to directed or random chemical modifications, such asacylation, alkylation, esterification, amidification to producestructural analogs.

Competitive screening assays may be done by combining KSP and a drugcandidate in a first sample. A second sample comprises a mitotic agent,KSP and a drug candidate. This may be performed in either the presenceor absence of microtubules. The binding of the drug candidate isdetermined for both samples, and a change, or difference in bindingbetween the two samples indicates the presence of an agent capable ofbinding to KSP and potentially modulating its activity. That is, if thebinding of the drug candidate is different in the second sample relativeto the first sample, the drug candidate is capable of binding to KSP.

In a preferred embodiment, the binding of the candidate agent isdetermined through the use of competitive binding assays. In thisembodiment, the competitor is a binding moiety known to bind to KSP,such as an antibody, peptide, binding partner, ligand, etc. Undercertain circumstances, there may be competitive binding as between thecandidate agent and the binding moiety, with the binding moietydisplacing the candidate agent.

In one embodiment, the candidate agent is labeled. Either the candidateagent, or the competitor, or both, is added first to KSP for a timesufficient to allow binding, if present. Incubations may be performed atany temperature which facilitates optimal activity, typically betweenabout 4 and about 40° C.

Incubation periods are selected for optimum activity, but may also beoptimized to facilitate rapid high throughput screening. Typicallybetween 0.1 and 1 hour will be sufficient. Excess reagent is generallyremoved or washed away. The second component is then added, and thepresence or absence of the labeled component is followed, to indicatebinding.

In a preferred embodiment, the competitor is added first, followed bythe candidate agent. Displacement of the competitor is an indication thecandidate agent is binding to KSP and thus is capable of binding to, andpotentially modulating, the activity of KSP. In this embodiment, eithercomponent can be labeled. Thus, for example, if the competitor islabeled, the presence of label in the wash solution indicatesdisplacement by the agent. Alternatively, if the candidate agent islabeled, the presence of the label on the support indicatesdisplacement.

In an alternative embodiment, the candidate agent is added first, withincubation and washing, followed by the competitor. The absence ofbinding by the competitor may indicate the candidate agent is bound toKSP with a higher affinity. Thus, if the candidate agent is labeled, thepresence of the label on the support, coupled with a lack of competitorbinding, may indicate the candidate agent is capable of binding to KSP.

It may be of value to identify the binding site of KSP. This can be donein a variety of ways. In one embodiment, once KSP has been identified asbinding to the mitotic agent, KSP is fragmented or modified and theassays repeated to identify the necessary components for binding.

Modulation is tested by screening for candidate agents capable ofmodulating the activity of KSP comprising the steps of combining acandidate agent with KSP, as above, and determining an alteration in thebiological activity of KSP. Thus, in this embodiment, the candidateagent should both bind to KSP (although this may not be necessary), andalter its biological or biochemical activity as defined herein. Themethods include both in vitro screening methods and in vivo screening ofcells for alterations in cell cycle distribution, cell viability, or forthe presence, morphology, activity, distribution, or amount of mitoticspindles, as are generally outlined above.

Alternatively, differential screening may be used to identify drugcandidates that bind to the native KSP, but cannot bind to modified KSP.

Positive controls and negative controls may be used in the assays.Preferably all control and test samples are performed in at leasttriplicate to obtain statistically significant results. Incubation ofall samples is for a time sufficient for the binding of the agent to theprotein. Following incubation, all samples are washed free ofnon-specifically bound material and the amount of bound, generallylabeled agent determined. For example, where a radiolabel is employed,the samples may be counted in a scintillation counter to determine theamount of bound compound.

A variety of other reagents may be included in the screening assays.These include reagents like salts, neutral proteins, e.g., albumin,detergents, etc which may be used to facilitate optimal protein-proteinbinding and/or reduce non-specific or background interactions. Alsoreagents that otherwise improve the efficiency of the assay, such asprotease inhibitors, nuclease inhibitors, anti-microbial agents, etc.,may be used. The mixture of components may be added in any order thatprovides for the requisite binding.

These and other aspects of the invention will be apparent from theteachings contained herein.

Assays

The compounds of the instant invention described in the Examples weretested by the assays described below and were found to have kinesininhibitory activity. Other assays are known in the literature and couldbe readily performed by those of skill in the art.

I. Kinesin ATPase In Vitro Assay

Cloning and Expression of Human Poly-Histidine Tagged KSP MotorDomain_(KSP(367H))

Plasmids for the expression of the human KSP motor domain construct werecloned by PCR using a pBluescript full length human KSP construct(Blangy et al., Cell, vol. 83, pp 1159-1169, 1995) as a template. TheN-terminal primer 5′-GCAACGATTAATATGGCGTCGCAGCCAAATTCGTCTGCGAAG(SEQ.ID.NO.: 1) and the C-terminal primer 5′-GCAACGCTCGAGTCAGTGATGATGGTGGTGATGCTGATTCACTTlCAGGCTTATTCAATAT (SEQ.D.NO.: 2) were used toamplify the motor domain and the neck linker region. The PCR productswere digested with AseI and XhoI, ligated into the NdeI/XhoI digestionproduct of pRSETa (Invitrogen) and transformed into E. coli BL21 (DE3).

Cells were grown at 37° C. to an OD₆₀₀ of 0.5. After cooling the cultureto room temperature expression of KSP was induced with 100 μM IPTG andincubation was continued overnight. Cells were pelleted bycentrifugation and washed once with ice-cold PBS. Pellets wereflash-frozen and stored −80° C.

Protein Purification

Cell pellets were thawed on ice and resuspended in lysis buffer (50 mMK-HEPES, pH 8.0, 250 mM KCl, 0.1% Tween, 10 mM imidazole, 0.5 mM Mg-ATP,1 mM PMSF, 2 mM benzimidine, 1× complete protease inhibitor cocktail(Roche)). Cell suspensions were incubated with 1 mg/ml lysozyme and 5 mMβ-mercaptoethanol on ice for 10 minutes, followed by sonication(3×30sec). All subsequent procedures were performed at 4° C. Lysateswere centrifuged at 40,000×g for 40 minutes. Supernatants were dilutedand loaded onto an SP Sepharose column (Pharmacia, 5 ml cartridge) inbuffer A (50 mM K-HEPES, pH 6.8, 1 mM. MgCI₂, 1 mM EGTA, 10 μM Mg-ATP, 1mM DIT) and eluted with a 0 to 750 mM KCl gradient in buffer A.Fractions containing KSP were pooled and incubated with Ni—NTA resin(Qiagen) for one hour. The resin was washed three times with buffer B(Lysis buffer minus PMSF and protease inhibitor cocktail), followed bythree 15-minute incubations and washes with buffer B. Finally, the resinwas incubated and washed for 15 minutes three times with buffer C (sameas buffer B except for pH 6.0) and poured into a column. KSP was elutedwith elution buffer (identical to buffer B except for 150 mM KCl and 250mM imidazole). KSP-containing fractions were pooled, made 10% insucrose, and stored at −80° C.

Microtubules are prepared from tubulin isolated from bovine brain.Purified tubulin (>97% MAP-free) at 1 mg/ml is polymerized at 37° C. inthe presence of 10 μM paclitaxel, 1 mM DTT, 1 mM GTP in BRB80 buffer (80mM K-PIPES, 1 mM EGTA, 1 mM MgCl₂ at pH 6.8). The resulting microtubulesare separated from non-polymerized tubulin by ultracentrifugation andremoval of the supernatant. The pellet, containing the microtubules, isgently resuspended in 10 μM paclitaxel, 1 mM DTT, 50 μg/ml ampicillin,and 5 μg/ml chloramphenicol in BRB80.

The kinesin motor domain is incubated with microtubules, 1 mM ATP (1:1MgCl₂: Na-ATP), and compound at 23° C. in buffer containing 80 mMK-HEPES (pH 7.0), 1 mM EGTA, 1 mM DTT, 1 mM MgCl₂, and 50 mM KCl. Thereaction is terminated by a 2-10 fold dilution with a final buffercomposition of 80 mM HEPES and 50 mM EDTA (or, alternately, with a 1:1addition of reaction volume to stop buffer (1.8M KCl and 50 mM EDTA)).Free phosphate from the ATP hydrolysis reaction is measured via aquinaldine redlammonium molybdate assay by adding a 1.5 times volume ofquench C (e.g., to a mixture of 40 μl reaction volume+40 μl stop bufferis then added 120 μl quench C). Quench A contains 0.1 mg/ml quinaldinered and 0.14% polyvinyl alcohol; quench B contains 12.3 mM ammoniummolybdate tetrahydrate in 1.15 M sulfuric acid. Quench C is a 2:1 ratioof quench A:quench B The reaction is incubated for 5-10 minutes at 23°C., and the absorbance of the phospho-molybdate complex is measured at540 nm.

The compounds 1-5 and 1-6 in the Examples were tested in the above assayand found to have an IC₅₀≦50 μM.

II. Cell Proliferation Assay

Cells are plated in 96-well tissue culture dishes at densities thatallow for logarithmic growth over the course of 24, 48, and 72 hours andallowed to adhere overnight. The following day, compounds are added in a10-point, one-half log titration to all plates. Each titration series isperformed in triplicate, and a constant DMSO concentration of 0.1% is.maintained throughout the assay. Controls of 0.1% DMSO alone are alsoincluded. Each compound dilution series is made in media without serum.The final concentration of serum in the assay is 5% in a 200 μL volumeof media. Twenty microliters of Alamar blue staining reagent is added toeach sample and control well on the titration plate at 24, 48, or 72hours following the addition of drug and returned to incubation at 37°C. Alamar blue fluorescence is analyzed 6-12 hours later on a CytoFluorII plate reader using 530-560 nanometer wavelength excitation, 590nanometer emission.

A cytotoxic EC₅₀ is derived by plotting compound concentration on thex-axis and average percent inhibition of cell growth for each titrationpoint on the y-axis. Growth of cells in control wells that have beentreated with vehicle alone is defined as 100% growth for the assay, andthe growth of cells treated with compounds is compared to this value.Proprietary in-house software is used to calculate percent cytotoxicityvalues and inflection points using logistic 4-parameter curve fitting.Percent cytotoxicity is defined as:%cytotoxicity:(Fluorescence_(control))−(Flourescence_(sample))×100×(Fluorescence_(control))⁻¹The inflection point is reported as the cytotoxic EC₅₀.III. Evaluation of Mitotic Arrest and Apoptosis by FACS

FACS analysis is used to evaluate the ability of a compound to arrestcells in mitosis and to induce apoptosis by measuring DNA content in atreated population of cells. Cells are seeded at a density of 1.4×10⁶cells per 6 cm² tissue culture dish and allowed to adhere overnight.Cells are then treated with vehicle (0.1% DMSO) or a titration series ofcompound for 8-16 hours. Following treatment, cells are harvested bytrypsinization at the indicated times and pelleted by centrifugation.Cell pellets are rinsed in PBS and fixed in 70% ethanol and stored at 4°C. overnight or longer.

For FACS analysis, at least 500,000 fixed cells are pelleted and the 70%ethanol is removed by aspiration. Cells are then incubated for 30 min at4° C. with RNase A (50 Kunitz units/mil) and propidium iodide (50μg/ml), and analyzed using a Becton Dickinson FACSCaliber. Data (from10,000 cells) is analyzed using the Modfit cell cycle analysis modelingsoftware (Verity Inc.).

An EC₅₀ for mitotic arrest is derived by plotting compound concentrationon the x-axis and percentage of cells in the G2/M phase of the cellcycle for each titration point (as measured by propidium iodidefluorescence) on the y-axis. Data analysis is performed using theSigmaPlot program to calculate an inflection point using logistic4-parameter curve fitting. The inflection point is reported as the EC₅₀for mitotic arrest. A similar method is used to determine the compoundEC₅₀ for apoptosis. Here, the percentage of apoptotic cells at eachtitration point (as determined by propidium iodide fluorescence) isplotted on the y-axis, and a similar analysis is carried out asdescribed above.

IV. Immunofluorescence Microscopy to Detect Monopolar Spindles

Methods for immunofluorescence staining of DNA, tubulin, and pericentrinare essentially as described in Kapoor et al. (2000) J. Cell Biol. 150:975-988. For cell culture studies, cells are plated on tissue culturetreated glass chamber slides and allowed to adhere overnight. Cells arethen incubated with the compound of interest for 4 to 16 hours. Afterincubation is complete, media and drug are aspirated and the chamber andgasket are removed from the glass slide. Cells are then permeabilized,fixed, washed, and blocked for nonspecific antibody binding according tothe referenced protocol. Paraffin-embedded tumor sections aredeparaffinized with xylene and rehydrated through an ethanol seriesprior to blocking. Slides are incubated in primary antibodies (mousemonoclonal anti-α-tubulin antibody, clone DM1A from Sigma diluted 1:500;rabbit polyclonal anti-pericentrin antibody from Covance, diluted1:2000) overnight at 4° C. After washing, slides are incubated withconjugated secondary antibodies (FITC-conjugated donkey anti-mouse IgGfor tubulin; Texas red-conjugated donkey anti-rabbit IgG forpericentrin) diluted to 15μg/ml for one hour at room temperature. Slidesare then washed and counterstained with Hoechst 33342 to visualize DNA.Immunostained samples are imaged with a 100× oil immersion objective ona Nikon epifluorescence microscope using Metamorph deconvolution andimaging software.

EXAMPLES

Examples provided are intended to assist in a further understanding ofthe invention. Particular materials employed, species and conditions areintended to be illustrative of the invention and not limiting of thereasonable scope thereof. Stereochemistry at centers of potentialchirality in the molecules shown is not depicted, since diastereomericmixtures are prepared by the methods described. It is understood thatone of ordinary skill in the art would be able to prepareenantiomerically pure compounds of the invention by starting with chiralreagents and by utilizing purification columns.

(−)-(5S,8aR)-7-(2,5-difluorophenyl)-5-phenyl-1,5,8,8a-tetrahydroindolizin-3(2H)-one((−)-(5S,8aR)-1-5) and(+)-(5S,8aR)-7-(2,5-difluorophenyl)-5-phenyl-1,5,6,8a-tetrahydroindolizin-3(2H)-one((+)-(5S,8aR)-1-6)

A solution of bicyclic piperdone 1-2 (0.155 g, 0.68 mmol) (Beckwith, A.L., Joseph, S. P., Mayadunne, R. T. J. Org. Chem. 1993, 58,4198-4199) inTHF (8 mL) was cooled to −78° C. and treated with a solution of NaHMDS(0.843 mL of a 1.0 M soln in THF). After stirring for 1 hr at −78° C.,neat Tf₂NPh was added. The reaction was stirred for 12 h with gradualwarming to rt. The reaction was quenched with satd aq NH₄Cl (10 mL) andthe mixture extracted with EtOAC (2×25 mL). The organic solution wasdried over MgSO₄, filtered, and concentrated to afford a mixture of 1-3and 1-4. The residue (0.244 g, 0.677 mmol) was dissolved in dioxane (5mL)/2.0 M aq Na₂CO₃ (1.0 mL) and the solution degassed with N₂(g). Thesolution was treated with with Pd(Ph₃P)₄ and 2,5-difluorophenylboronicacid (0.139 g, 0.88 mmol) and heated at 90° C for 40 min. The rxn wascooled to rt, quenched with satd aq NH₄Cl (5 mL) and extracted withEtOAc(2×25 mL). The organic solution was dried over MgSO₄, filtered andconcentrated. The residue was purified by flash chromatography (SiO₂;50/50 EtOAc/hexanes) to afford a 2:1 mixture of racemic 1-5 and racemic1-6. This mixture was purified by chiral BPLC (ChiralPak AD; 90/10Hexanes/iPrOH; 5×50 cm, 60 mL/min) to provide a mixture of(5R,8aS)-1-5/racemic-1-6 (RT=37.2 min) and enantiomerically pure(−)-(5S,8aR)-1-5 (RT=44.5 min). The RT=37.2 min component was purifiedby chiral HPLC (ChiralPak AS; 90/10 to 50/50 Hexanes/EtOH over 90 min;5×50 cm) to afford enantiomerically pure (+)-(5S,8aR)-1-6 (RT=89.7 min).

Data for (−)-(5S,8aR)-1-5: ¹HNMR (500 MHz, CDCl₃) δ 7.45-7.30 (m, 5H),7.06-6.14 (m, 1H), 5.76(m, 1H), 3.89 (m, 1H), 2.64 (m, 1H), 2.47 (m,2H), 2.31 (m 1H), 1.82 (m, 1H) 1.28 (m, 1H) ppm.

Data for (+)-(5S,8aR)-1-6: ¹HNMR (500 MHz, CDCl₃) δ 7.46-7.29 (m, 5H),7.12-6.96 (m, 3H), 5.96 (s, 1H), 5.69 (s, 1H), 3.07 (m, 1H), 2.92 (m,1H), 2.52 (m, 2H), 2.33 (M, 1H), 1.79 (m, 1H) ppm.

1. A compound of Formula I:

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ais 0 or 1; b is 0 or 1; m is 0, 1, or 2; n is 0 or 1; r is 0 or 1; s is0 or 1; u is 2, 3, 4or 5; v is 1, 2or 3; a dashed line represents anoptional double bond, provided that one and only one double bond ispresent in the ring; X is selected from: —(CR⁸R⁸)_(v)—, —SO₂—, —SO— and—C(═O)—; Y is selected from: O, N(R^(c)), S, —C(═O)—, —CR⁸R⁸—,—N(R^(c))C(═O)— and —N(R^(c))CR⁸R⁸—; or p1 X and Y are combined to form—C(R⁸)═C(R⁸)—; Z is selected from: —C(═O)—, —C(═S)—, —SO₂—, —SO— and—C(R⁸)(R⁹)—; or Y and Z are combined to form —N═C(R⁸)—; R¹ and R⁴ areindependently selected from: 1) aryl, 2) C₁-C₆ aralkyl, 3) C₃-C₈cycloalkyl, and 4) heterocyclyl, said aryl, cycloalkyl, aralkyl andheterocyclyl is optionally substituted with one or more substituentsselected from R¹⁰; R², R^(3a), R^(3b), R⁵, R⁶ and R⁷ are independentlyselected from: 1) H, 2) C₁-C₁₀ alkyl, 3) aryl, 4) C₂-C₁₀ alkenyl, 5)C₂-C₁₀ alkynyl, 6) C₁-C₆ perfluoroalkyl, 7) C₁-C₆ aralkyl, 8) C₃-C₈cycloalkyl, and 9) heterocyclyl, said alkyl, aryl, alkenyl, alkynyl,cycloalkyl, aralkyl and heterocyclyl is optionally substituted with oneor more substituents selected from R¹⁰; or R^(3a) and R^(3b) or R⁵ andR⁶ attached to the same carbon atom are combined to form —(CH₂)_(u)—wherein one of the carbon atoms is optionally replaced by a moietyselected from O, S(O)_(m), —N(R^(a))C(O)—, —N(R^(b))— and —N(COR^(a))—;R⁸ and R⁹ is independently selected from: 1) H, 2) (C═O)_(a)O_(b)C₁-C₁₀alkyl, 3) (C═O)_(a)O_(b)aryl, 4) C₂-C₁₀ alkenyl, 5) C₂-C₁₀ alkynyl, 6)(C═O)_(a)O_(b) heterocyclyl, 7) CO₂H, 8) halo, 9) CN, 10) OH, 11)O_(b)C₁-C₆ perfluoroalkyl, 12) O_(a)(C═O)_(b)NR¹²R¹³, 13) S(O)_(m)R^(a),14) S(O)₂NR¹²R¹³, 15) CHO, 16) (N═O)R¹²R¹³, and 17) (C═O)_(a)O_(b)C₃-C₈cycloalkyl, said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, andcycloalkyl optionally substituted with one or more substituents selectedfrom R¹¹; R¹⁰ is independently selected from: 1) (C═O)_(a)O_(b)C₁-C₁₀alkyl, 2) (C═O)_(a)O_(b)aryl, 3) C₂-C₁₀ alkenyl, 4) C₂-C₁₀ alkynyl, 5)(C═O)_(a)O_(b) heterocyclyl, 6) CO₂H, 7) halo, 8) CN, 9) OH, 10)O_(b)C₁-C₆ perfluoroalkyl, 11) O_(a)(C═O)_(b)NR¹²R¹³, 12) S(O)_(m)R^(a),13) S(O)₂NR¹²R¹³, 14) oxo, 15) CHO, 16) (N═O)R¹²R¹³, 17)(C═O)_(a)O_(b)C₃-C₈ cycloalkyl, and 18) —OPO(OH)₂; said alkyl, aryl,alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substitutedwith one or more substituents selected from R¹¹; R¹¹ is selectedfrom: 1) (C═O)_(r)O_(s)(C₁-C₁₀)alkyl, 2) O_(r)(C₁-C₃)perfluoroalkyl, 3)(C₀-C₆)alkylene-S(O)_(m)R^(a), 4) oxo, 5) OH, 6) halo, 7) CN, 8)(C═O)_(r)O_(s)(C₂-C₁₀)alkenyl, 9) (C═O)_(r)O_(s)(C₂-C₁₀)alkynyl, 10)(C═O)_(r)O_(s)(C₃-C₆)cycloalkyl, 11) (C═O)_(r)O_(s)(C₀-C₆)alkylene-aryl,12) (C═O)_(r)O_(s)(C₀-C₆)alkylene-heterocyclyl, 13)(C═O)_(r)O_(s)(C₀-C₆)alkylene-N(R^(b))₂, 14) C(O)R^(a), 15)(C₀-C₆)alkylene-CO₂R^(a), 16) C(O)H, 17) (C₀-C₆)alkylene-CO₂H, 18)C(O)N(R^(b))₂, 19) S(O)_(m)R^(a), 20) S(O)₂N(R^(b))₂ and 21) —OPO(OH)₂;said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylene andheterocyclyl is optionally substituted with up to three substituentsselected from R^(b), OH, (C₁-C₆)alkoxy, halogen, CO₂H, CN, O(C═O)C₁-C₆alkyl, oxo, and N(R^(b))₂; R¹² and R¹³ are independently selectedfrom: 1) H, 2) (C═O)O_(b)C₁-C₁₀ alkyl, 3) (C═O)O_(b)C₃-C₈ cycloalkyl, 4)(C+O)O_(b)aryl, 5) (C═O)O_(b)heterocyclyl, 6) C₁-C₁₀ alkyl, 7) aryl, 8)C₂-C₁₀ alkenyl, 9) C₂-C₁₀ alkynyl, 10) heterocyclyl, 11) C₃-C₈cycloalkyl, 12) SO₂R^(a), and 13) (C═O)NR^(b) ₂, said alkyl, cycloalkyl,aryl, heterocylyl, alkenyl, and alkynyl is optionally substituted withone or more substituents selected from R¹¹, or R¹² and R¹³ can be takentogether with the nitrogen to which they are attached to form amonocyclic or bicyclic heterocycle with 3-7 members in each ring andoptionally containing, in addition to the nitrogen, one or twoadditional heteroatoms selected from N, O and S, said monocyclic orbicyclic heterocycle optionally substituted with one or moresubstituents selected from R¹¹; R¹⁴ is independently selected from: 1)(C═O)_(a)O_(b)C₁-C₁₀ alkyl, 2) (C═O)_(a)O_(b)aryl, 3) C₂-C₁₀ alkenyl, 4)C₂-C₁₀ alkynyl, 5) (C═O)_(a)O_(b) heterocyclyl, 6) CO₂H, 7) halo, 8) CN,9) OH, 10) O_(b)C₁-C₆ perfluoroalkyl, 11) O_(a)(C═O)_(b)NR¹²R¹³, 12)S(O)_(m)R^(a), 13) S(O)₂NR¹²R¹³, 14) oxo, 15) CHO, 16) (N═O)R¹²R¹³, 17)(C═O)_(a)O_(b)C₃-C₈ cycloalkyl, and 18) —OPO(OH)₂; said alkyl, aryl,alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substitutedwith one or more substituents selected from R¹¹; R^(a) is (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, aryl, or heterocyclyl, optionally substituted withone to three substituents selected from R¹⁴; R^(b) is H, (C₁-C₆)alkyl,aryl, heterocyclyl, (C₃-C₆)cycloalkyl, (C═O)OC₁-C₆ alkyl, (C═O)C₁-C₆alkyl or S(O)₂R^(a), optionally substituted with one to threesubstituents selected from R¹⁴; R^(c) and R^(c′) are independentlyselected from: H, (C₁-C₆)alkyl, aryl, heterocyclyl and(C₃-C₆)cycloalkyl, optionally substituted with one, two or threesubstituents selected from R¹⁰, or R^(c) and R^(c′) can be takentogether with the nitrogen to which they are attached to form amonocyclic or bicyclic heterocycle with 3-7 members in each ring andoptionally containing, in addition to the nitrogen, one or twoadditional heteroatoms selected from N, O and S, said monocyclic orbicyclic heterocycle optionally substituted with one, two or threesubstituents selected from R¹¹; R^(d) and R^(d′) are independentlyselected from: (C₁-C₆)alkyl, (C₁-C₆)alkoxy and NR^(b) ₂, or R^(d) andR^(d′) can be taken together with the phosphorous to which they areattached to form a monocyclic heterocycle with 5-7 members the ring andoptionally containing, in addition to the phosphorous, one or twoadditional heteroatoms selected from NR^(e), O and S, said monocyclicheterocycle optionally substituted with one, two or three substituentsselected from R¹¹; and R^(e) is selected from: H and (C₁-C₆)alkyl. 2.The compound according to claim 1 of the Formula II:

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:a is 0 or 1; b is 0 or 1; m is 0, 1, or 2; n is 0 or 1; r is 0 or 1; sis 0 or 1; X is selected from —CH₂— and —CH₂CH₂—; Y is selected from: O,N(R^(c)), S, —C(═O)—, —CH(R⁸)—, —N(R^(c))C(═O)— and —N(R^(c))CH(R⁸)—; Zis selected from: —C(═O)—, —C(═S)—, —SO₂— and —C(R⁸)(R⁹)—, R¹ and R⁴ areindependently selected from: 1) aryl, 2) C₁-C₆ aralkyl, 3) C₃-C₈cycloalkyl, and 4) heterocyclyl, said aryl, cycloalkyl, aralkyl andheterocyclyl is optionally substituted with one or more substituentsselected from R¹⁰; R² is selected from: 1) H, 2) C₁-C₁₀ alkyl, 3) aryl,4) C₂-C₁₀ alkenyl, 5) C₂-C₁₀ alkynyl, 6) C₁-C₆ perfluoroalkyl, 7) C₁-C₆aralkyl, 8) C₃-C₈ cycloalkyl, and 9) heterocyclyl, said alkyl, aryl,alkenyl, alkynyl, cycloalkyl, aralkyl and heterocyclyl is optionallysubstituted with one or more substituents selected from R¹⁰; R^(3a) andR⁵ are independently selected from: 1) H, 2) C₁-C₁₀ alkyl, 3) C₁-C₆perfluoroalkyl, 4) C₁-C₆ aralkyl, said alkyl and aralkyl is optionallysubstituted with one or more substituents selected from R¹⁰; R⁸ and R⁹is independently selected from: 1) H, 2) (C═O)_(a)O_(b)C₁-C₁₀ alkyl, 3)(C═O)_(a)O_(b)aryl, 4) (C═O)_(a)O_(b) heterocyclyl, 5) CO₂H, 6) halo, 7)CN, 8) OH, 9) O_(b)C₁-C₆ perfluoroalkyl, 10) O_(a)(C═O)_(b)NR¹²R¹³, and11) (C═O)_(a)O_(b)C₃-C₈ cycloalkyl, said alkyl, aryl, heterocyclyl, andcycloalkyl optionally substituted with one or more substituents selectedfrom R¹¹; R¹⁰ is independently selected from: 1) (C═O)_(a)O_(b)C₁-C₁₀alkyl, 2) (C═O)_(a)O_(b)aryl, 3) C₂-C₁₀ alkenyl, 4) C₂-C₁₀ alkynyl, 5)(C═O)_(a)O_(b) heterocyclyl, 6) CO₂H, 7) halo, 8) CN, 9) OH, 10)O_(b)C₁-C₆ perfluoroalkyl, 11) O_(a)(C═O)_(b)NR¹²R¹³, 12) S(O)_(m)R^(a),13) S(O)₂NR¹²R¹³, 14) oxo, 15) CHO, 16) (N═O)R¹²R¹³, 17)(C═O)_(a)O_(b)C₃-C₈ cycloalkyl, and 18) —OPO(OH)₂; said alkyl, aryl,alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substitutedwith one, two or three substituents selected from R¹¹; R¹¹ is selectedfrom: 1) (C═O)_(r)O_(s)(C₁-C₁₀)alkyl, 2) O_(r)(C₁-C₃)perfluoroalkyl, 3)oxo, 4) OH, 5) halo, 6) CN, 7) (C₂-C₁₀)alkenyl, 8) (C₂-C₁₀)alkynyl, 9)(C═O)_(r)O_(s)(C₃-C₆)cycloalkyl, 10) (C═O)_(r)O_(s)(C₀-C₆)alkylene-aryl,11) (C═O)_(r)O_(s)(C₀-C₆)alkylene-heterocyclyl, 12)(C═O)_(r)O_(s)(C₀-C₆)alkylene-N(R^(b))₂, 13) C(O)R^(a), 14)(C₀-C₆)alkylene-CO₂R^(a), 15) C(O)H, 16) (C₀-C₆)alkylene-CO₂H, and 17)C(O)N(R^(b))₂, 18) S(O)_(m)R_(a), 19) S(O)₂N(R^(b))₂; and 20) —OPO(OH)₂;said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylene andheterocyclyl is optionally substituted with up to three substituentsselected from R^(b), OH, (C₁-C₆)alkoxy, halogen, CO₂H, CN, O(C═O)C₁-C₆alkyl, oxo, and N(R^(b))₂; R¹² and R¹³ are independently selectedfrom: 1) H, 2) (C═O)O_(b)C₁-C₁₀ alkyl, 3) (C═O)O_(b)C₃-C₈ cycloalkyl, 4)(C═O)O_(b)aryl, 5) (C═O)O_(b)heterocyclyl, 6) C₁-C₁₀ alkyl, 7) aryl, 8)C₂-C₁₀ alkenyl, 9) C₂-C₁₀ alkynyl, 10) heterocyclyl, 11) C₃-C₈cycloalkyl, 12) SO₂R^(a), and 13) (C═O)NR^(b) ₂, said alkyl, cycloalkyl,aryl, heterocylyl, alkenyl, and alkynyl is optionally substituted withone, two or three substituents selected from R¹¹, or R¹² and R¹³ can betaken together with the nitrogen to which they are attached to form amonocyclic or bicyclic heterocycle with 5-7 members in each ring andoptionally containing, in addition to the nitrogen, one or twoadditional heteroatoms selected from N, O and S, said monocyclic orbicyclic heterocycle optionally substituted with one, two or threesubstituents selected from R¹¹; R^(a) is (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, aryl, or heterocyclyl; R^(b) is H, (C₁-C₆)alkyl,aryl, heterocyclyl, (C₃-C₆)cycloalkyl, (C═O)OC₁-C₆ alkyl, (C═O)C₁-C₆alkyl or S(O)₂R^(a); R^(c) and R^(c′) are independently selected from:H, (C₁-C₆)alkyl, aryl, heterocyclyl and (C₃-C₆)cycloalkyl; or R^(c) andR^(c′) can be taken together with the nitrogen to which they areattached to form a monocyclic or bicyclic heterocycle with 5-7 membersin each ring and optionally containing, in addition to the nitrogen, oneor two additional heteroatoms selected from N, O and S, said monocyclicor bicyclic heterocycle optionally substituted with one, two or threesubstituents selected from R¹¹; R^(d) and R^(d′) are independentlyselected from: (C₁-C₆)alkyl, (C₁-C₆)alkoxy and NR^(b) ₂, or R^(d) andR^(d′) can be taken together with the phosphorous to which they areattached to form a monocyclic heterocycle with 5-7 members the ring andoptionally containing, in addition to the phosphorous, one or twoadditional heteroatoms selected from NR^(e), O and S, said monocyclicheterocycle optionally substituted with one, two or three substituentsselected from R¹¹; and R^(e) is selected from: H and (C₁-C₆)alkyl. 3.The compound according to claim 2 of Formula III:

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:a is 0 or 1; b is 0 or 1; m is 0, 1, or 2; n is 0 or 1 ; r is 0 or 1; sis 0 or 1; X is selected from —CH₂— and —CH₂CH₂—; Y is selected from: O,N(R^(c)), S, —C(═O)—, —CH(R⁸)—, —N(R^(c))C(═O)— and —N(R^(c))CH(R⁸)—; Zis selected from: —C(═O)—, —C(═S)—, —SO₂— and —C(R⁸)(R⁹)—, R¹ and R⁴ areindependently selected from: 1) aryl, 2) C₁-C₆ aralkyl, 3) C₃-C₈cycloalkyl, and 4) heterocyclyl, said aryl, cycloalkyl, aralkyl andheterocyclyl is optionally substituted with one or more substituentsselected from R¹⁰; R² is selected from: 1) H, 2) C₁-C₁₀ alkyl, 3) aryl,4) C₂-C₁₀ alkenyl, 5) C₂-C₁₀ alkynyl, 8) C₁-C₆ perfluoroalkyl, 9) C₁-C₆aralkyl, 8) C₃-C₈ cycloalkyl, and 9) heterocyclyl, said alkyl, aryl,alkenyl, alkynyl, cycloalkyl, aralkyl and heterocyclyl is optionallysubstituted with one or more substituents selected from R¹⁰; R^(3a) andR⁵ are independently selected from: 1) H, 2) C₁-C₁₀ alkyl, 3) C₁-C₆perfluoroalkyl, 4) C₁-C₆ aralkyl, said alkyl and aralkyl is optionallysubstituted with one or more substituents selected from R¹⁰; R⁸ and R⁹is independently selected from: 1) H, 2) (C═O)_(a)O_(b)C₁-C₁₀ alkyl, 3)(C═O)_(a)O_(b)aryl, 4) (C═O)_(a)O_(b) heterocyclyl, 5) CO₂H, 6) halo, 7)CN, 8) OH, 9) O_(b)C₁-C₆ perfluoroalkyl, 10) O_(a)(C═O)_(b)NR¹²R¹³, and11) (C═O)_(a)O_(b)C₃-C₈ cycloalkyl, said alkyl, aryl, heterocyclyl, andcycloalkyl optionally substituted with one or more substituents selectedfrom R¹¹; R¹⁰ is independently selected from: 17) (C═O)_(a)O_(b)C₁-C₁₀alkyl, 18) (C═O)_(a)O_(b)aryl, 19) C₂-C₁₀ alkenyl, 20) C₂-C₁₀ alkynyl,21) (C═O)_(a)O_(b) heterocyclyl, 22) CO₂H, 23) halo, 24) CN, 25) OH, 26)O_(b)C₁-C₆ perfluoroalkyl, 27) O_(a)(C═O)_(b)NR¹²R¹³, 28) S(O)_(m)R_(a),29) S(O)₂NR¹²R¹³, 30) oxo, 31) CHO, 32) (N═O)R¹²R¹³, 17)(C=O)_(a)O_(b)C₃-C₈ cycloalkyl, and 18) —OPO(OH)₂; said alkyl, aryl,alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substitutedwith one, two or three substituents selected from R¹¹; R¹¹ is selectedfrom: 1) (C═O)_(r)O_(s)(C₁-C₁₀)alkyl, 2) O_(r)(C₁-C₃)perfluoroalkyl, 3)oxo, 4) OH, 5) halo, 6) CN, 7) (C₂-C₁₀)alkenyl, 8) (C₂-C₁₀)alkynyl, 9)(C═O)_(r)O_(s)(C₃-C₆)cycloalkyl, 10) (C═O)_(r)O_(s)(C₀-C₆)alkylene-aryl,11) (C═O)_(r)O_(s)(C₀-C₆)alkylene-heterocyclyl, 12)(C═O)_(r)O_(s)(C₀-C₆)alkylene-N(R^(b))₂, 13) C(O)R^(a), 14)(C₀-C₆)alkylene-CO₂R^(a), 15) C(O)H, 16) (C₀-C₆)alkylene-CO₂H, and 17)C(O)N(R^(b))₂, 18) S(O)_(m)R^(a), 19) S(O)₂N(R^(b))₂; and 20) —OPO(OH)₂;said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylene andheterocyclyl is optionally substituted with up to three substituentsselected from R^(b), OH, (C₁-C₆)alkoxy, halogen, CO₂H, CN, O(C═O)C₁-C₆alkyl, oxo, and N(R^(b))₂; R¹² and R¹³ are independently selectedfrom: 1) H, 2) (C═O)O_(b)C₁-C₁₀ alkyl, 3) (C═O)O_(b)C₃-C₈ cycloalkyl, 4)(C═O)O_(b)aryl, 5) (C═O)O_(b)heterocyclyl, 6) C₁-C₁₀ alkyl, 7) aryl, 8)C₂-C₁₀ alkenyl, 9) C₂-C₁₀ alkynyl, 10) heterocyclyl, 11) C₃-C₈cycloalkyl, 12) SO₂R^(a), and 13) (C═O)NR^(b) ₂, said alkyl, cycloalkyl,aryl, heterocylyl, alkenyl, and alkynyl is optionally substituted withone, two or three substituents selected from R¹¹, or R¹² and R¹³ can betaken together with the nitrogen to which they are attached to form amonocyclic or bicyclic heterocycle with 5-7 members in each ring andoptionally containing, in addition to the nitrogen, one or twoadditional heteroatoms selected from N, O and S, said monocyclic orbicyclic heterocycle optionally substituted with one, two or threesubstituents selected from R¹¹; R^(a) is (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, aryl, or heterocyclyl; R^(b) is H, (C₁-C₆)alkyl,aryl, heterocyclyl, (C₃-C₆)cycloalkyl, (C═O)OC₁-C₆ alkyl, (C═O)C₁-C₆alkyl or S(O)₂R^(a); R^(c) and R^(c′) are independently selected from:H, (C₁-C₆)alkyl, aryl, heterocyclyl and (C₃-C₆)cycloalkyl; or R^(c) andR^(c′) can be taken together with the nitrogen to which they areattached to form a monocyclic or bicyclic heterocycle with 5-7 membersin each ring and optionally containing, in addition to the nitrogen, oneor two additional heteroatoms selected from N, O and S, said monocyclicor bicyclic heterocycle optionally substituted with one, two or threesubstituents selected from R¹¹; R^(d) and R^(d′) are independentlyselected from: (C₁-C₆)alkyl, (C₁-C₆)alkoxy and NR^(b) ₂, or R^(d) andR^(d′) can be taken together with the phosphorous to which they areattached to form a monocyclic heterocycle with 5-7 members the ring andoptionally containing, in addition to the phosphorous, one or twoadditional heteroatoms selected from NR^(e), O and S, said monocyclicheterocycle optionally substituted with one, two or three substituentsselected from R¹¹; and R^(e) is selected from: H and (C₁-C₆)alkyl. 4.The compound according to claim 3 of the Formula IV,

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ais 0 or 1; b is 0 or 1; m is 0, 1, or 2; r is 0 or 1; s is 0 or 1; X isselected from —CH₂— and —CH₂CH₂—; Y is selected from: O, N(R^(c)) and—CH(R⁸)—; Z is selected from: —C(═O)—, —C(═S)—, —SO₂— and —C(R⁸)(R⁹)—,R¹ is selected from: 1) aryl, 2) C₁-C₆ aralkyl, 3) C₃-C₈ cycloalkyl, and4) heterocyclyl, said aryl, cycloalkyl, aralkyl and heterocyclyl isoptionally substituted with one or more substituents selected from R¹⁰;R² is selected from: 1) H, 2) C₁-C₁₀ alkyl, 3) aryl, 4) C₂-C₁₀ alkenyl,5) C₂-C₁₀ alkynyl, 6) C₁-C₆ perfluoroalkyl, 7) C₁-C₆ aralkyl, 8) C₃-C₈cycloalkyl, and 9) heterocyclyl, said alkyl, aryl, alkenyl, alkynyl,cycloalkyl, aralkyl and heterocyclyl is optionally substituted with oneor more substituents selected from R¹⁰; R⁸ and R⁹ is independentlyselected from: 1) H, 2) (C═O)_(a)O_(b)C₁-C₁₀ alkyl, 3) CO₂H, 4) halo, 5)OH, 6) O_(a)(C═O)_(b)NR¹²R¹³, and 7) (C═O)_(a)O_(b)C₃-C₈ cycloalkyl,said alkyl, aryl, heterocyclyl, and cycloalkyl optionally substitutedwith one or more substituents selected from R¹¹; R¹⁰ is independentlyselected from: 1) (C═O)_(a)O_(b)C₁-C₁₀ alkyl, 2) (C═O)_(a)O_(b)aryl, 3)C₂-C₁₀ alkenyl, 4) C₂-C₁₀ alkynyl, 5) (C═O)_(a)O_(b)heterocyclyl, 6)CO₂H, 7) halo, 8) CN, 9) OH, 10) O_(b)C₁-C₆ perfluoroalkyl, 11)O_(a)(C═O)_(b)NR¹²R¹³, 12) S(O)_(m)R_(a), 13) S(O)₂NR¹²R¹³, 14) oxo, 15)CHO, 16) (N═O)R¹²R¹³, 17) (C═O)_(a)O_(b)C₃-C₈ cycloalkyl, and 18)—OPO(OH)₂; said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, andcycloalkyl optionally substituted with one, two or three substituentsselected from R¹¹; R^(10′) is halogen; R¹¹ is selected from: 1)(C═O)_(r)O_(s)(C₁-C₁₀)alkyl, 2) O_(r)(C₁-C₃)perfluoroalkyl, 3) oxo, 4)OH, 5) halo, 6) CN, 7) (C₂-C₁₀)alkenyl, 8) (C₂-C₁₀)alkynyl, 9)(C═O)_(r)O_(s)(C₃-C₆)cycloalkyl, 10) (C═O)_(r)O_(s)(C₀-C₆)alkylene-aryl,11) (C═O)_(r)O_(s)(C₀-C₆)alkylene-heterocyclyl, 12)(C═O)_(r)O_(s)(C₀-C₆)alkylene-N(R^(b))₂, 13) C(O)R^(a), 14)(C₀-C₆)alkylene-CO₂R^(a), 15) C(O)H, 16) (C₀-C₆)alkylene-CO₂H, and 17)C(O)N(R^(b))₂, 18) S(O)_(m)R^(a), 19) S(O)₂N(R^(b))₂; and 20) —)PO(OH)₂;said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl isoptionally substituted with up to three substituents selected fromR^(b), OH, (C₁-C₆)alkoxy, halogen, CO₂H, CN, O(C═O)C₁-C₆ alkyl, oxo, andN(R^(b))₂; R¹² and R¹³ are independently selected from: 1) H, 2)(C═O)O_(b)C₁-C₁₀ alkyl, 3) (C═O)O_(b)C₃-C₈ cycloalkyl, 4)(C═O)O_(b)aryl, 5) (C═O)O_(b)heterocyclyl, 6) C₁-C₁₀ alkyl, 7) aryl, 8)C₂-C₁₀ alkenyl, 9) C₂-C₁₀ alkynyl, 10) heterocyclyl, 11) C₃-C₈cycloalkyl, 12) SO₂R^(a), and 13) (C═O)NR^(b) ₂, said alkyl, cycloalkyl,aryl, heterocylyl, alkenyl, and alkynyl is optionally substituted withone, two or three substituents selected from R¹¹, or R¹² and R¹³ can betaken together with the nitrogen to which they are attached to form amonocyclic or bicyclic heterocycle with 5-7 members in each ring andoptionally containing, in addition to the nitrogen, one or twoadditional heteroatoms selected from N, O and S, said monocyclic orbicyclic heterocycle optionally substituted with one, two or threesubstituents selected from R¹¹; R^(a) is (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, aryl, or heterocyclyl; R^(b) is H, (C₁-C₆)alkyl,aryl, heterocyclyl, (C₃-C₆)cycloalkyl, (C═O)OC₁-C₆ alkyl, (C═O)C₁-C₆alkyl or S(O)₂R^(a); R^(c) and R^(c′) are independently selected from:H, (C₁-C₆)alkyl, aryl, heterocyclyl and (C₃-C₆)cycloalkyl; or R^(c) andR^(c′) can be taken together with the nitrogen to which they areattached to form a monocyclic or bicyclic heterocycle with 5-7 membersin each ring and optionally containing, in addition to the nitrogen, oneor two additional heteroatoms selected from N, O and S, said monocyclicor bicyclic heterocycle optionally substituted with one, two or threesubstituents selected from R¹¹; R^(d) and R^(d′) are independentlyselected from: (C₁-C₆)alkyl, (C₁-C₆)alkoxy and NR^(b) ₂, or R^(d) andR^(d′) can be taken together with the phosphorous to which they areattached to form a monocyclic heterocycle with 5-7 members the ring andoptionally containing, in addition to the phosphorous, one or twoadditional heteroatoms selected from NR^(e), O and S, said monocyclicheterocycle optionally substituted with one, two or three substituentsselected from R¹¹; and R^(e) is selected from: H and (C₁-C₆)alkyl. 5.The compound according to claim 4 of the Formula V,

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ais 0 or 1; b is 0 or 1; m is 0, 1, or 2; r is 0 or 1; s is 0 or 1; X isselected from —CH₂— and —CH₂CH₂—; Y is selected from: O, N(R^(c)) and—CH(R⁸)—; Z is selected from: —C(═O)—, —C(═S)—, —SO₂— and —C(R⁸)(R⁹)—,R² is selected from: 2) H, 2) C₁-C₁₀ alkyl, 3) aryl, 4) C₂-C₁₀ alkenyl,5) C₂-C₁₀ alkynyl, 10) C₁-C₆ perfluoroalkyl, 11) C₁-C₆ aralkyl, 12)C₃-C₈ cycloalkyl, and 13) heterocyclyl, said alkyl, aryl, alkenyl,alkynyl, cycloalkyl, aralkyl and heterocyclyl is optionally substitutedwith one or more substituents selected from R¹⁰; R⁸and R⁹isindependently selected from: 1) H, 2) (C═O)_(a)O_(b)C₁-C₁₀ alkyl, 3)CO₂H, 4) halo, 5) OH, 6) O_(a)(C═O)_(b)NR¹²R¹³, and 7)(C═O)_(a)O_(b)C₃-C₈ cycloalkyl, said alkyl, aryl, heterocyclyl, andcycloalkyl optionally substituted with one or more substituents selectedfrom R¹¹; R¹⁰ is independently selected from: 17) (C═O)_(a)O_(b)C₁-C₁₀alkyl, 18) (C═O)_(a)O_(b)aryl, 19) C₂-C₁₀ alkenyl, 20) C₂-C₁₀ alkynyl,21) (C═O)_(a)O_(b) heterocyclyl, 22) CO₂H, 23) halo, 24) CN, 25) OH, 26)O_(b)C₁-C₆ perfluoroalkyl, 27) O_(a)(C═O)_(b)NR¹²R¹³, 28) S(O)_(m)R^(a),29) S(O)₂NR¹²R¹³, 30) oxo, 31) CHO, 32) (N═O)R¹²R¹³, 17)(C═O)_(a)O_(b)C₃-C₈ cycloalkyl, and 19) —OPO(OH)₂; said alkyl, aryl,alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substitutedwith one, two or three substituents selected from R¹¹; R^(10′) ishalogen; R¹¹ is selected from: 1) (C═O)_(r)O_(s)(C₁-C₁₀)alkyl, 2)O_(r)(C₁-C₃)perfluoroalkyl, 3) oxo, 4) OH, 5) halo, 6) CN, 7)(C₂-C₁₀)alkenyl, 8) (C₂-C₁₀)alkynyl, 9) (C═O)_(r)O_(s)(C₃-C₆)cycloalkyl,10) (C═O)_(r)O_(s)(C₀-C₆)alkylene-aryl, 11)(C═O)_(r)O_(s)(C₀-C₆)alkylene-heterocyclyl, 12)(C═O)_(r)O_(s)(C₀-C₆)alkylene-N(R^(b))₂, 13) C(O)R^(a), 14)(C₀-C₆)alkylene-CO₂R^(a), 15) C(O)H, 16) (C₀-C₆)alkylene-CO₂H, and 17)C(O)N(R^(b))₂, 18) S(O)_(m)R^(a), 19) S(O)₂N(R^(b))₂; and 20) —OPO(OH)₂;said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl isoptionally substituted with up to three substituents selected fromR^(b), OH, (C₁-C₆)alkoxy, halogen, CO₂H, CN, O(C═O)C₁-C₆ alkyl, oxo, andN(R^(b))₂; R¹² and R¹³ are independently selected from: 1) H, 2)(C═O)O_(b)C₁-C₁₀ alkyl, 3) (C═O)O_(b)C₃-C₈ cycloalkyl, 4)(C═O)O_(b)aryl, 5) (C═O)O_(b)heterocyclyl, 6) C₁-C₁₀ alkyl, 7) aryl, 8)C₂-C₁₀ alkenyl, 9) C₂-C₁₀ alkynyl, 10) heterocyclyl, 11) C₃-C₈cycloalkyl, 12) SO₂R^(a), and 13) (C═O)NR^(b) ₂, said alkyl, cycloalkyl,aryl, heterocylyl, alkenyl, and alkynyl is optionally substituted withone, two or three substituents selected from R¹¹, or R¹² and R¹³ can betaken together with the nitrogen to which they are attached to form amonocyclic or bicyclic heterocycle with 5-7 members in each ring andoptionally containing, in addition to the nitrogen, one or twoadditional heteroatoms selected from N, O and S, said monocyclic orbicyclic heterocycle optionally substituted with one, two or threesubstituents selected from R¹¹; R^(a) is (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, aryl, or heterocyclyl; R^(b) is H, (C₁-C₆)alkyl,aryl, heterocyclyl, (C₃-C₆)cycloalkyl, (C═O)OC₁-C₆ alkyl, (C═O)C₁-C₆alkyl or S(O)₂R^(a); R^(c) and R^(c′) are independently selected from:H, (C₁-C₆)alkyl, aryl, heterocyclyl and (C₃-C₆)cycloalkyl; or R^(c) andR^(c′) can be taken together with the nitrogen to which they areattached to form a monocyclic or bicyclic heterocycle with 5-7 membersin each ring and optionally containing, in addition to the nitrogen, oneor two additional heteroatoms selected from N, O and S, said monocyclicor bicyclic heterocycle optionally substituted with one, two or threesubstituents selected from R¹¹; R^(d) and R^(d′) are independentlyselected from: (C₁-C₆)alkyl, (C₁-C₆)alkoxy and NR^(b) ₂, or R^(d) andR^(d′) can be taken together with the phosphorous to which they areattached to form a monocyclic heterocycle with 5-7 members the ring andoptionally containing, in addition to the phosphorous, one or twoadditional heteroatoms selected from NR^(e), O and S, said monocyclicheterocycle optionally substituted with one, two or three substituentsselected from R¹¹; and R^(e) is selected from: H and (C₁-C₆)alkyl.
 6. Acompound selected from:(−)-(5S,8aR)-7-(2,5-difluorophenyl)-5-phenyl-1,5,8,8a-tetrahydroindolizin-3(2H)-oneand (+)-(5S,8aR)-7-(2,5-difluorophenyl)-5-phenyl-1,5,6,8a-tetrahydroindolizin-3(2H)-one or a pharmaceutically acceptablesalt or stereoisomer thereof.
 7. A pharmaceutical composition that iscomprised of a compound in accordance with claim 1 and apharmaceutically acceptable carrier.
 8. A method of treating orpreventing cancer in a mammal in need of such treatment that iscomprised of administering to said mammal a therapeutically effectiveamount of a compound of claim
 1. 9. A method of treating cancer orpreventing cancer in accordance with claim 8 wherein the cancer isselected from cancers of the brain, genitourinary tract, lymphaticsystem, stomach, larynx and lung.
 10. A method of treating or preventingcancer in accordance with claim 8 wherein the cancer is selected fromhistiocytic lymphoma, lung adenocarcinoma, small cell lung cancers,pancreatic cancer, gioblastomas and breast carcinoma.
 11. (canceled) 12.(canceled)
 13. (canceled)
 14. (canceled)
 15. (canceled)
 16. (canceled)17. (canceled)
 18. (canceled)
 19. (canceled)
 20. A method of treatingcancer which comprises administering a therapeutically effective amountof a compound of claim 1 in combination with radiation therapy.
 21. Amethod of treating or preventing cancer that comprises administering atherapeutically effective amount of a compound of claim 1 in combinationwith a compound selected from: 1) an estrogen receptor modulator, 2) anandrogen receptor modulator, 3) a retinoid receptor modulator, 4) acytotoxic/cytostatic agent, 5) an antiproliferative agent, 6) aprenyl-protein transferase inhibitor, 7) an HMG-CoA reductase inhibitor,8) an HIV protease inhibitor, 9) a reverse transcriptase inhibitor, 10)an angiogenesis inhibitor, 11) PPAR-γ agonists, 12) PPAR-δ agonists, 13)an inhibitor of inherent multidrug resistance, 14) an anti-emetic agent,15) an agent useful in the treatment of anemia, 16) an agent useful inthe treatment of neutropenia, 17) an immunologic-enhancing drug, 18) aninhibitor of cell proliferation and survival signaling, and 19) an agentthat interfers with a cell cycle checkpoint.
 22. A method of treatingcancer that comprises administering a therapeutically effective amountof a compound of claim 1 in combination with radiation therapy and acompound selected from: 1) an estrogen receptor modulator, 2) anandrogen receptor modulator, 3) a retinoid receptor modulator, 4) acytotoxic/cytostatic agent, 5) an antiproliferative agent, 6) aprenyl-protein transferase inhibitor, 7) an HMG-CoA reductase inhibitor,8) an HIV protease inhibitor, 9) a reverse transcriptase inhibitor, 10)an angiogenesis inhibitor, 11) PPAR-γ agonists, 12) PPAR-δ agonists, 13)an inhibitor of inherent multidrug resistance, 14) an anti-emetic agent,15) an agent useful in the treatment of anemia, 16) an agent useful inthe treatment of neutropenia, 17) an immunologic-enhancing drug, 18) aninhibitor of cell proliferation and survival signaling, and 19) an agentthat interfers with a cell cycle checkpoint.
 23. A method of treating orpreventing cancer which comprises administering a therapeuticallyeffective amount of a compound of claim 1 and paclitaxel or trastuzumab.24. (canceled)
 25. (canceled)
 26. (canceled)
 27. A method of treating orpreventing cancer which comprises administering a therapeuticallyeffective amount of a compound of claim 1 in combination with aproteosome inhibitor.
 28. A method of treating or preventing cancerwhich comprises administering a therapeutically effective amount of acompound of claim 1 in combination with an aurora kinase inhibitor. 29.(canceled)
 30. A method of treating or preventing cancer which comprisesadministering a therapeutically effective amount of a compound of claim1 in combination with a serine/threonine kinase inhibitor.
 31. A methodof treating or preventing cancer which comprises administering atherapeutically effective amount of a compound of claim 1 in combinationwith an inhibitor of a mitotic kinesin that is not KSP.
 32. A method ofmodulating mitotic spindle formation which comprises administering atherapeutically effective amount of a compound of claim
 1. 33. A methodof inhibiting the mitotic kinesin KSP which comprises administering atherapeutically effective amount of a compound of claim 1.